Nitrogen containing heterocyclic compounds and medicines containing the same

ABSTRACT

Compounds represented by the following general formula: 
                         
[wherein X 1 , X 2 , X 3  and X 4  each independently represent a single bond, C 1-6  alkylene, etc.; A 2  represents optionally substituted phenyl, etc.; A 1  represents an optionally substituted 5- to 7-membered heterocyclic group containing —C(=Q 1 )- (wherein Q 1  represents oxygen, sulfur or ═N—R 11  (wherein R 11  represents hydrogen or C 1-6  alkyl)) and nitrogen, etc.; and Z 1  represents piperidin-diyl, etc.],
 
salts thereof and hydrates of the foregoing.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application11/173,099, filed Jul. 1, 2005, now U.S. Pat. No. 7,265,108 which claimsthe benefit of U.S. patent application 10/388,185, filed Mar. 12, 2003,and issued as U.S. Pat. No. 6,995,144, which claims priority to JP2002-069529 filed Mar. 14, 2002, the entirety of each of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to nitrogen containing heterocycliccompounds having sodium channel-inhibiting effects, salts thereof andhydrates of the foregoing, to process for producing the same and to theuse of the same as medicine.

2. Related Background Art

Compounds with sodium channel-inhibiting effect are known to be usefulfor treatment of various types of neuralgia (for example, postherpeticneuralgia, diabetic neuralgia, HIV neuralgia, etc.).

As compounds with sodium channel-inhibiting effect there may bementioned Lidocaine, Carbamazepine, Mexiletine, Amitriptyline and thelike, which are already used as neuralgia treatment agents. For example,Lidocaine is used for treatment of postherpetic neuralgia, andCarbamazepine is used for treatment of trigeminal neuralgia.

It has also been reported that Mexiletine and Lidocaine are effective asanalgesics (Pain. 83 (1999) 389-400; European Journal of Pain. 2 (1998)3-14; Pain. 73 (1997) 123-139).

Compounds with sodium channel-inhibiting activity have been reported toalso exhibit the following pharmacological activities and therapeuticeffects for diseases other than types of neuralgia.

(i) Compounds with sodium channel-inhibiting activity are used fortreatment of epilepsy (Pharmacology & Therapeutics 90 (2001) 21-34).

(ii) It has been reported that Carbamazepine, used as an anticonvulsant,is effective for treatment of manic-depressive psychosis (BiologicalPsychiatry 51 (2002) 253-260).

(iii) It has been reported that Lidocaine and Mexiletine are effectivefor various symptoms of multiple sclerosis (Journal of NeurologicalSciences 162 (1999) 162-168).

(iv) It has been reported that Lidocaine is effective for treatment ofpremature ejaculation (Andrologia 34 (2002) 356-359).

(v) Somnolence-inducing effects have been reported for Carbamazepine andOxocarbazepine which are used as anticonvulsants (Epilepsy 46 (2002)145-155; CNS Drugs 15 (2001) 137-163), suggesting the possibility of theuse of sodium channel inhibitors for treatment of insomnia.

(vi) Activity by sodium channel inhibitors in various neuropathic animalmodels has been reported, suggesting a protective effect againstneuropathy in cerebrovascular disease, cranial injuries and spinalinjuries (Trends in Pharmacological Sciences 16 (1995) 309-316).

(vii) The efficacy of sodium channel inhibitors in Parkinson's diseasemodel animals has been published at a scientific conference (31st AnnualMeeting of Society of Neuroscience 27 (2001) Abstract 199.16).

Low-molecular weight compounds with sodium channel-inhibiting effectshave also been reported, such as the following.

Sodium channel-inhibiting compounds represented by the following generalformula (I¹):

(WO01/53288).

These sodium channel inhibitors, however, exhibit effects on thecardiovascular system and inhibition effect on hepatic drug metabolizingenzymes, and have therefore been less than satisfactory.

SUMMARY OF THE INVENTION

As explained above, it has been desirable to develop drugs that exhibitexcellent sodium channel-inhibiting effect, which satisfy the drugrequirements for pharmacological activity and safety (in terms ofeffects on the cardiovascular system, inhibiting effect on hepatic drugmetabolizing enzymes, enzyme induction, etc.), and which performeffectively in the clinic. It is therefore an object of the presentinvention to search for and discover such excellent sodiumchannel-inhibiting compounds.

As a result of much vigorous and dedicated research conducted in lightof the circumstances described above, the present inventors havediscovered novel nitrogen containing heterocyclic compounds which haveexcellent sodium channel-inhibiting effect and excellent safety.

The present invention provides:

<1> A compound represented by the following general formula:

[wherein X¹ and X² each independently represent a single bond,optionally substituted C₁₋₆ alkylene, optionally substituted C₃₋₈cycloalkylene, an optionally substituted monocyclic 4- to 8-memberednon-aromatic heterocyclic group, optionally substituted C₂₋₆ alkenylene,optionally substituted C₂₋₆ alkynylene, oxygen, —CO—, —S—, —S(O)—,—S(O)₂—, —CONR⁷²—, —NR⁷²CO—, —S(O)₂NR⁷²—, —NR⁷²S(O)₂— or —NR⁷²—;R⁷² represents hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₂₋₇ acyl or optionally substituted C₃₋₈cycloalkyl;X³ and X⁴ each independently represent a single bond, optionallysubstituted C₁₋₆ alkylene, optionally substituted C₂₋₆ alkenylene,optionally substituted C₂₋₆ alkynylene, optionally substituted C₃₋₈cycloalkylene, an optionally substituted monocyclic 4- to 8-memberednon-aromatic heterocyclic group, an optionally substituted 5- to10-membered aromatic heterocyclic group, oxygen, —CO—, —CS—, —S—,—S(O)—, —S(O)₂—, —COCH₂—, —CH₂CO—, —O—CH₂—, —CH₂O—, —CONR⁷¹—, —NR⁷¹CO—,—S(O)₂NR⁷¹—, —NR⁷¹S(O)₂—, —NR⁷¹— or —C(═N—OR⁷⁰)— (wherein R⁷⁰ representshydrogen or optionally substituted C₁₋₆ alkyl);R⁷¹ represents hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₂₋₇ acyl, optionally substituted C₃₋₈ cycloalkylor optionally substituted benzoyl;Z¹ represents an optionally substituted monocyclic or bicyclic 4- to12-membered non-aromatic heterocyclic group (wherein at least onenitrogen atom is included among the atoms forming the ring);A² represents optionally substituted phenyl, optionally substituted1-naphthyl, optionally substituted 2-naphthyl, an optionally substituted5- to 10-membered aromatic heterocyclic group, an optionally substituted9- to 11-membered benzene fused ring group or an optionally substituted9- to 11-membered aromatic heterocycle fused ring group; andA¹ represents (1) an optionally substituted 5- to 7-memberedheterocyclic group containing —C(=Q¹)- and nitrogen (wherein Q¹represents oxygen, sulfur or ═N—R¹¹ (wherein R¹¹ represents hydrogen orC₁₋₆ alkyl)),(2) an optionally substituted group of the formula:

(wherein Q¹ has the same definition as above, R²¹ represents hydrogen orC₁₋₆ alkyl, and u represents 0 or 1), or (3) a 5- to 10-memberedaromatic heterocyclic group having at least one group selected from thegroup consisting of optionally substituted C₁₋₆ alkoxy, C₁₋₆ alkylthio,hydroxyl, mercapto and—NR¹³R¹⁴ (wherein R¹³ and R¹⁴ each independently represent hydrogen orC₁₋₆ alkyl), and also having other optional substituents],a salt thereof or a hydrate of the foregoing;<2> a compound according to <1>, a salt of the compound or a hydrate ofthe foregoing, wherein Z¹ is a monocyclic or bicyclic 4- to 12-memberednon-aromatic heterocyclic group optionally having 1 to 3 groups selectedfrom the group consisting of (1) C₁₋₆ alkyl optionally having 1 to 3substituents selected from the group consisting of hydroxyl, C₁₋₆alkoxy, C₁₋₆ alkyl, amino, halogen and cyano, (2) phenyl-C₁₋₆ alkyloptionally having 1 to 3 substituents selected from the group consistingof hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, amino, halogen and cyano, (3)phenyloxy-C₁₋₆ alkyl optionally having 1 to 3 substituents selected fromthe group consisting of hydroxyl, C₁₋₆ alkoxy, C₁₋₅ alkyl, amino,halogen and cyano, (4) hydroxyl, (5) C₁₋₆ alkoxy, (6) halogen, (7)cyano, (8) C₂₋₇ alkoxycarbonyl, and the formulas:

(wherein R³¹, R³² and R³³ each independently represent hydrogen or C₁₋₆alkyl) and at least one nitrogen atom is included among the atomsforming the ring;<2-2> a compound according to <1>, a salt of the compound or a hydratesof the foregoing, wherein Z¹ is a monocyclic or bicyclic 4- to12-membered non-aromatic heterocyclic group optionally having 1 groupselected from the group consisting of (1) C₁₋₆ alkyl optionally having1-3 substituents selected from the group consisting of hydroxyl, C₁₋₆alkoxy, C₁₋₆ alkyl, amino, halogen and cyano, (2) phenyl-C₁₋₆ alkyloptionally having 1-3 substituents selected from the group consisting ofhydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, amino, halogen and cyano, (3)phenyloxy-C₁₋₆ alkyl optionally having 1-3 substituents selected fromthe group consisting of hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, amino,halogen and cyano, (4) hydroxyl, (5) C₁₋₅ alkoxy, (6) halogen, (7)cyano, (8) C₂₋₇ alkoxycarbonyl, and the formulas:

(wherein R³¹, R³² and R³³ each independently represent hydrogen or C₁₋₆alkyl) (with the proviso that Z¹ contains at least one nitrogen atomamong the atoms of the ring);<3> a compound according to <1> or <2>, a salt of the compound or ahydrate of the foregoing, wherein the monocyclic or bicyclic 4- to12-membered non-aromatic heterocyclic group is azetidine-diyl,pyrrolidine-diyl, piperidine-diyl, azepane-diyl, piperazine-diyl, or agroup represented by the formula:

<4> a compound according to <1>, a salt of the compound or a hydrate ofthe foregoing, wherein Z¹ is a group represented by the formula:

(wherein R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ eachindependently represent (1) hydrogen, (2) halogen, (3) cyano, (4)hydroxyl, (5) C₂₋₇ alkoxycarbonyl, (6) C₁₋₆ alkyl optionally substitutedwith 1 to 4 groups selected from the group consisting of hydroxyl, C₁₋₆alkoxy and halogen, (7) C₁₋₆ alkoxy optionally substituted with 1 to 4groups selected from the group consisting of hydroxyl, C₁₋₆ alkoxy andhalogen, (8) 2-methylphenyloxymethyl or (9) 2-fluorophenyloxymethyl,wherein R⁵⁰ and R⁵¹ may together form a carbonyl group, R⁵² and R⁵³ maytogether form a carbonyl group and R⁵⁵ and R⁵⁶ may together form acarbonyl group);<5> a compound according to <1>, a salt of the compound or a hydrate ofthe foregoing, wherein Z¹ is a group represented by the formula:

(wherein R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ have the same definitions as R⁵¹,R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ in <4>);<6> a compound according to <5>, a salt of the compound or a hydrate ofthe foregoing, wherein R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ each independentlyrepresent (1) hydrogen, (2) hydroxyl, (3) halogen, (4) alkyl, (5) cyanoor (6) hydroxymethyl;<7> a compound according to <5> or <6>, a salt of the compound or ahydrate of the foregoing, wherein at least one of R⁵¹, R⁵³, R⁵⁴, R⁵⁵ andR⁵⁷ is not hydrogen;<7-2> a compound according to <5> or <6>, a salt of the compound or ahydrate of the foregoing, wherein at least three of R⁵¹, R⁵³, R⁵⁴, R⁵⁵and R⁵⁷ are hydrogen atoms;<8> a compound according to <5> or <6>, a salt of the compound or ahydrate of the foregoing, wherein at least four of R⁵¹, R⁵³, R⁵⁴, R⁵⁵and R⁵⁷ are hydrogen;<9> a compound according to <5>, a salt of the compound or a hydrate ofthe foregoing, wherein all of R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ are hydrogen;<10> a compound according to any one of <1> to <9>, a salt of thecompound or a hydrate of the foregoing, wherein X¹ is a single bond, andX² is optionally substituted C₁₋₆ alkylene;<11> a compound according to any one of <1> to <9>, a salt of thecompound or a hydrate of the foregoing, wherein X¹ is a single bond, andX² is methylene, 1,2-ethylene or 1,1-ethylene;<12> a compound according to any one of <1> to <11>, a salt of thecompound or a hydrate of the foregoing, wherein —X³—X⁴— is methylene,oxygen, a single bond or a group represented by the formula:

(wherein X⁴⁰ represents (1) methylene optionally having 1 or 2 groupsselected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy and cyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)— or (6)—S(O)₂—;X⁴¹ represents methylene optionally having 1 or 2 groups selected fromthe group consisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy andcyano;R³⁴ represents C₁₋₆ alkyl;R⁴¹ represents (1) phenyl optionally having 1 to 3 groups selected fromthe group consisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy andcyano, (2) phenyl-C₁₋₆ alkyl optionally having 1 to 3 groups selectedfrom the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxyand cyano or (3) C₁₋₆ alkyl optionally having 1 to 3 groups selectedfrom the group consisting of halogen, hydroxyl, C₁₋₆ alkoxy and cyano;andR⁴² represents (1) C₁₋₆ alkyl optionally having 1 to 3 groups selectedfrom the group consisting of halogen, hydroxyl, C₁₋₆ alkoxy and cyano or(2) hydrogen);<13> a compound according to any one of <1> to <11>, a salt of thecompound or a hydrate of the foregoing, wherein —X³—X⁴— is a grouprepresented by the formula:

(wherein X⁴² represents (1) methylene optionally having one groupselected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy and cyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)—, (6)—S(O)₂— or (7) —CF₂—, and X⁴³ represents either methylene optionallyhaving one group selected from the group consisting of halogen,hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy and cyano, or —CF₂—);<14> a compounds according to any one of <1> to <11>, a salt of thecompound or a hydrate of the foregoing, wherein —X³—X⁴— is a grouprepresented by the formula:

(wherein X⁴⁴ represents either methylene optionally having 1 groupselected from the group consisting of fluorine, hydroxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy and cyano);<14-2> a compound according to any one of <1> to <11>, a salt of thecompound or a hydrate of the foregoing, wherein —X³—X⁴— is a grouprepresented by the formula:

(wherein X⁴⁵ represents either methylene optionally having one groupselected from the group consisting of fluorine, hydroxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy and cyano, or —CF₂—);<15> a compound according to any one of <1> to <11>, a salt of thecompound or a hydrate of the foregoing, wherein —X³—X⁴— is a grouprepresented by the formula:

<16> a compound according to any one of <1> to <15>, a salt of thecompound or a hydrate of the foregoing, wherein A² is phenyl optionallyhaving 1 to 3 substituents selected from Substituent Group A below,1-naphthyl optionally having 1 to 3 substituents selected fromSubstituent Group A below, 2-naphthyl optionally having 1 to 3substituents selected from Substituent Group A below, a 5- to10-membered aromatic heterocyclic group optionally having 1 to 3substituents selected from Substituent Group A below, a 9- to11-membered benzene fused ring group optionally having 1 to 3substituents selected from Substituent Group A below or a 9- to11-membered aromatic heterocycle fused ring group optionally having 1 to3 substituents selected from Substituent Group A below;<Substituent Group A>

The group consisting of C₁₋₆ alkyl optionally having 1 to 3 substituentsselected from Substituent Group B below, C₁₋₆ alkoxy optionally having 1to 3 substituents selected from Substituent Group B below, halogen, C₃₋₈cycloalkyl, C₂₋₇ alkoxycarbonyl, C₂₋₇ acyl, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, cyano, nitro, phenyl, pyridyl,ethylenedioxy, methylenedioxy, a group represented by the formula:

(wherein t1 and t2 each independently represent an integer of 0 to 3,and R⁸⁰ represents hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl), and a grouprepresented by the formula:

(wherein R⁷³ and R⁷⁴ each independently represent hydrogen, C₁₋₆ alkyl,C₂₋₇ acyl, C₁₋₆ alkylsulfonyl, —CO—NR⁷⁵R⁷⁶ or —CS—NR⁷⁵R⁷⁶, and R¹⁵ andR⁷⁶ each independently represent hydrogen or C₁₋₆ alkyl);<Substituent Group B>

The group consisting of halogen, C₁₋₆ alkoxy, cyano, hydroxyl and C₃₋₈cycloalkyl;

<17> a compound according to any one of <1> to <15>, a salt of thecompound or a hydrate of the foregoing, wherein A² is a monovalent groupderived by removing a hydrogen atom from a compound represented by theformula:

and A² optionally has 1 to 3 substituents selected from SubstituentGroup A in <16>;<18> a compound according to any one of <1> to <15>, a salt of thecompound or a hydrate of the foregoing, wherein A² is a monovalent groupderived by removing a hydrogen atom from a compound represented by theformula:

and A² optionally has 1 to 3 substituents selected from SubstituentGroup A in <16>;<19> a compound according to any one of <16> to <18>, a salt of thecompound or a hydrate of the foregoing, wherein Substituent Group A in<16> is the group consisting of halogen, C₁₋₆ alkyl optionally having 1to 3 substituents selected from Substituent Group B in <16>, C₁₋₆ alkoxyoptionally having 1 to 3 substituents selected from Substituent Group Bin <16>, C₃₋₈ cycloalkyl, C₁₋₆ alkylthio and a group represented by theformula:

(wherein t1 and t2 each independently represent an integer of 0 to 3,and R⁸⁰ represents hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl);<20> a compound according to any one of <1> to <15>, a salt of thecompound or a hydrate of the foregoing, wherein A² is a grouprepresented by the formula:

(wherein R⁸¹ represents (1) C₁₋₆ alkyl optionally having 1 to 3substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl and C₁₋₆ alkoxy, (2) C₁₋₆ alkoxy optionally having 1 to 3substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl and C₁₋₆ alkoxy, (3) hydrogen, (4) C₁₋₆ alkylthio optionallyhaving 1 to 3 substituents selected from the group consisting ofhalogen, C₃₋₈ cycloalkyl and C₁₋₆ alkoxy or (5) halogen);<21> a compound according to any one of <1> to <15>, a salt of thecompound or a hydrate of the foregoing, wherein A² is a grouprepresented by the formula:

<22> a compound according to any one of <1> to <21>, a salt of thecompound or a hydrate of the foregoing, wherein A¹ is a grouprepresented by the formula:

(wherein R²⁰ and R²¹ each independently represent hydrogen or C₁₋₆alkyl, R⁶¹, R⁶², R⁶³ and R⁶⁴ each independently represent hydrogen,halogen, optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆alkyl or cyano, and Q¹ has the same definition as Q¹ in <1>);<23> a compound according to any one of <1> to <21>, a salt of thecompound or a hydrate of the foregoing, wherein A¹ is a grouprepresented by the formula:

(wherein R²⁰ and R²³ each independently represent hydrogen of C₁₋₆alkyl, R⁶¹, R⁶², R⁶³ and R⁶⁴ each independently represent hydrogen,halogen, optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆alkyl or cyano, and Q¹ has the same definition as Q¹ in <1>);<24> a compound according to <22> or <23>, a salt of the compound or ahydrate of the foregoing, wherein Q¹ is oxygen;<25> a compound according to any one of <1> to <21>, a salt of thecompound or a hydrate of the foregoing, wherein A¹ is a grouprepresented by the formula:

(wherein R²¹, R⁶¹ and R⁶² have the same definitions as R²¹, R⁶¹ and R⁶²in <22>, and R²² represents hydrogen, C₁₋₆ alkyl, benzyl,p-methoxybenzyl or dimethoxybenzyl);<26> a compound according to any one of <1> to <21>, a salt of thecompound or a hydrate of the foregoing, wherein A¹ is a grouprepresented by the formula:

(wherein R²¹ represents hydrogen or C₁₋₆ alkyl, and R^(61a), R^(62a) andR^(63a) each independently represent hydrogen, halogen, C₁₋₆ alkoxy,C₁₋₆ alkyl or cyano);<27> a compound according to any one of <1> to <21>, a salt of thecompound or a hydrate of the foregoing, wherein A¹ is a grouprepresented by the formula:

(wherein R²¹, R^(61a) and R^(62a) have the same definitions as R²¹,R^(61a) and R^(62a) in <26>);<28> a compound according to any one of <1> to <21>, a salt of thecompound or a hydrate of the foregoing, wherein A¹ is a grouprepresented by the formula:

(wherein R²¹, R^(61a) and R^(62a) have the same definitions as R²¹,R^(61a) and R^(62a) in <26>);<29> a compound according to any one of <22> to <28>, a salt of thecompound or a hydrate of the foregoing, wherein R²¹ is hydrogen;<30> a compound according to any one of <22> to <25>, a salt of thecompound or a hydrate of the foregoing, wherein R⁶¹ and R⁶² arehydrogen;<31> a compound according to any one of <26> to <29>, a salt of thecompound or a hydrate of the foregoing, wherein R^(61a) and R^(62a) arehydrogen;<32> a compound according to <1>, a salt of the compound or a hydrate ofthe foregoing, wherein the compound is a compound selected from thegroup consisting of6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one,(E)-3-[4-[2-(3-methyl-2-thienyl)vinyl]piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-(2,3-dihydrobenzofuran-7-yl)ethyl]piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-(2-methylphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-(2-methoxyphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-[2-(trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-[2-fluoro-6-(trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one,cis-3-[4-[2-(2-fluorophenyl)acetyl]-2-methylpiperidino]methyl-1H-pyrazin-2-one,3-[4-[2-(2-fluorophenyl)acetyl]-4-methylpiperidino]methyl-1H-pyrazin-2-one,3-[4-methyl-4-[2-[2-(trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one,3-[1-[4-[2-(2-fluorophenyl)acetyl]piperidino]ethyl]-1H-pyrazin-2-one,3-[1-[4-[2-[2-(trifluoromethyl)phenyl]acetyl]piperidino]ethyl]-1H-pyrazin-2-one,3-[4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one,3-[4-(2-methoxyphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one,3-[4-(2-methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one,3-[4-[2-(2-ethoxyphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one and3-[4-[2-[2-(methylthio)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one;<33> a sodium channel inhibitor comprising a compound according to anyone of <1> to <32>, a salt thereof or a hydrate of the foregoing;<34> an analgesic agent comprising a compound according to any one of<1> to <32>, a salt thereof or a hydrate of the foregoing;<35> a therapeutic or prophylactic agent for neuralgia comprising acompound according to any one of <1> to <32>, a salt thereof or ahydrate of the foregoing;<36> a therapeutic or prophylactic agent for diabetic neuralgia, HIVneuralgia, postherpetic neuralgia, trigeminal neuralgia, stump pain,post spinal injury pain, thalamic pain or post-stroke pain, comprising acompound according to any one of <1> to <32>, a salt thereof or ahydrate of the foregoing;<37> a therapeutic or prophylactic agent for pain or neuropathy,comprising a compound according to any one of <1> to <32>, a saltthereof or a hydrate of the foregoing;<38> a therapeutic or prophylactic agent for low back pain,radiculopathy, inflammatory pain, arthralgia, postoperative pain, cancerpain, acute cerebrovascular disorder-induced neuropathy, cranialinjury-induced neuropathy, spinal injury-induced neuropathy, Parkinson'sdisease, multiple sclerosis, epilepsy, insomnia, premature ejaculationor manic-depressive psychosis, comprising a compound according to anyone of <1> to <32>, a salt thereof or a hydrate of the foregoing;<39> a therapeutic or prophylactic method for a disease or neuralgia forwhich sodium channel inhibition is effective, comprising administeringto a patient, a pharmacologically effective dose of a compound accordingto any one of <1> to <32>, a salt thereof or a hydrate of the foregoing;<40> the use of a compound according to any one of <1> to <32>, a saltthereof or a hydrate of the foregoing for the manufacture of atherapeutic or prophylactic agent for a disease or neuralgia for whichsodium channel inhibition is effective.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be explained in detail.

Many of the structural formulas for the compounds throughout the presentspecification represent only one isomeric form for convenience, but theinvention encompasses any and all of the geometric isomers as well asoptical isomers based on asymmetric carbons, stereoisomers andtautomers, and mixtures of those isomers, which are implied by thestructures of the compounds, without being limited to any of theformulas shown for convenience. The compounds of the invention thereforeinclude all those having asymmetric carbons therein and existing inoptically active or racemic form, with no particular restrictions on theinvention. There are also no restrictions when polymorphic crystallineforms thereof exist, and the compounds may be in one crystalline form ora mixture of different crystalline forms, while anhydrides and hydratesof the compounds of the invention are also included. Also encompassedwithin the scope of the invention are metabolic products of thecompounds of the invention, produced by decomposition of the compoundsin the body.

The definitions of the terms and symbols used throughout the presentspecification will now be explained for more detailed description of theinvention.

The term “C₁₋₆ alkyl” as used throughout the present specificationrefers to a C₁₋₆ linear or branched alkyl group which is a monovalentgroup derived by removing a hydrogen atom from a C₁₋₆ aliphatichydrocarbon, and as specific examples there may be mentioned methyl,ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl,1-butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl,2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl,3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl,3-methyl-3-pentyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2,2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3,3-dimethyl-2-butyl,2,3-dimethyl-2-butyl, and the like.

The term “C₂₋₆ alkenyl” as used throughout the present specificationrefers to a C₂₋₆ linear or branched alkenyl group, and as specificexamples there may be mentioned vinyl, allyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, pentenyl, hexenyl, and the like.

The term “C₂₋₆ alkynyl” as used throughout the present specificationrefers to a C₂₋₆ linear or branched alkynyl group, and as specificexamples there may be mentioned ethynyl, 1-propynyl, 2-propynyl,butynyl, pentynyl, hexynyl, and the like.

The term “C₃₋₈ cycloalkyl” as used throughout the present specificationrefers to a C₃₋₈ cyclic aliphatic hydrocarbon group, and as specificexamples there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “C₁₋₆ alkylene” as used throughout the present specificationrefers to a divalent group derived by further removing a hydrogen atomfrom the aforementioned “C₁₋₆ alkyl” group, and as specific examplesthere may be mentioned methylene, 1,2-ethylene, 1,1-ethylene,1,3-propylene, tetramethylene, pentamethylene, hexamethylene, and thelike.

The term “C₂₋₆ alkenylene” as used throughout the present specificationrefers to a divalent group derived by further removing a hydrogen atomfrom the aforementioned “C₂₋₆ alkenyl” group, and as specific examplesthere may be mentioned vinylene, propenylene, butenylene, pentenylene,hexenylene, and the like.

The term “C₂₋₆ alkynylene” as used throughout the present specificationrefers to a divalent group derived by further removing a hydrogen atomfrom the aforementioned “C₂₋₆ alkynyl” group, and as specific examplesthere may be mentioned ethynylene, propynylene, butynylene, pentynylene,hexynylene, and the like.

The term “C₃₋₈ cycloalkylene” as used throughout the presentspecification refers to a divalent group derived by further removing ahydrogen atom from the aforementioned “C₃₋₈ cycloalkyl” group.

The term “C₁₋₆ alkoxy” as used throughout the present specificationrefers to a group having an oxy group bonded to the aforementioned “C₁₋₆alkyl” group, and as specific examples there may be mentioned methoxy,ethoxy, 1-propyloxy, 2-propyloxy, 2-methyl-1-propyloxy,2-methyl-2-propyloxy, 1-butyloxy, 2-butyloxy, 1-pentyloxy, 2-pentyloxy,3-pentyloxy, 2-methyl-1-butyloxy, 3-methyl-1-butyloxy,2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy,1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentyloxy,3-methyl-1-pentyloxy, 4-methyl-1-pentyloxy, 2-methyl-2-pentyloxy,3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy,3-methyl-3-pentyloxy, 2,3-dimethyl-1-butyloxy, 3,3-dimethyl-1-butyloxy,2,2-dimethyl-1-butyloxy, 2-ethyl-1-butyloxy, 3,3-dimethyl-2-butyloxy,2,3-dimethyl-2-butyloxy, and the like.

The term “C₁₋₆ alkylthio” as used throughout the present specificationrefers to a group having a thio group bonded to the aforementioned “C₁₋₆alkyl” group, and as specific examples there may be mentionedmethylthio, ethylthio, 1-propylthio, 2-propylthio, butylthio,pentylthio, and the like.

The term “C₁₋₆ alkylsulfinyl” as used throughout the presentspecification refers to a group having a sulfinyl group bonded to theaforementioned “C₁₋₆ alkyl” group, and as specific examples there may bementioned methylsulfinyl, ethylsulfinyl, 1-propylsulfinyl,2-propylsulfinyl, butylsulfinyl, pentylsulfinyl, and the like.

The term “C₁₋₆ alkylsulfonyl” as used throughout the presentspecification refers to a group having a sulfonyl group bonded to theaforementioned “C₁₋₆ alkyl” group, and as specific examples there may bementioned methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl,2-propylsulfonyl, butylsulfonyl, pentylsulfonyl, and the like.

The term “C₂₋₇ acyl” as used throughout the present specification refersto a group having a carbonyl group bonded to the aforementioned “C₁₋₆alkyl” group, and as specific examples there may be mentioned acetyl,propionyl, isopropionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl, and the like.

The term “C₂₋₇ alkoxycarbonyl” as used throughout the presentspecification refers to a group having a carbonyl group bonded to theaforementioned “C₁₋₆ alkoxy” group, and as specific examples there maybe mentioned methoxycarbonyl, ethoxycarbonyl, 1-propyloxycarbonyl,2-propyloxycarbonyl, and the like.

The term “halogen atom” as used throughout the present specificationrefers to fluorine, chlorine, bromine or iodine.

The term “hetero atom” as used throughout the present specificationrefers to sulfur, oxygen or nitrogen.

The term “5- to 10-membered aromatic heterocycle” as used throughout thepresent specification refers to an aromatic ring having 5 to 10 atoms inthe ring and containing one or more hetero atoms among the atoms of thering, and as specific examples there may be mentioned pyridine,thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, triazole, pyrazole, furazan, thiadiazole, oxadiazole,pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, indazole,chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline,naphthylidine, phthalazine, purine, pteridine, thienofuran,imidazothiazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,benzothiadiazole, benzimidazole, imidazopyridine, pyrrolopyridine,pyrrolopyrimidine, pyridopyrimidine, and the like.

The term “5- to 10-membered aromatic heterocyclic group” as usedthroughout the present specification refers to a monovalent or divalentgroup derived by removing 1 or 2 hydrogen atoms from any desiredposition of the aforementioned “5- to 10-membered aromatic heterocycle”.

The term “monocyclic 4- to 8-membered non-aromatic heterocycle” as usedthroughout the present specification refers to

-   (1) a monocyclic non-aromatic ring,-   (2) having 4 to 8 atoms in the ring,-   (3) containing 1 or 2 hetero atoms among the atoms of the ring,-   (4) optionally including 1 or 2 double bonds in the ring, and-   (5) optionally including 1 to 3 carbonyl groups in the ring.

As specific examples of monocyclic 4- to 8-membered non-aromaticheterocycles there may be mentioned azetidine, pyrrolidine, piperidine,azepane, azocane, tetrahydrofuran, tetrahydropyran, morpholine,thiomorpholine, piperazine, thiazolidine, dioxane, imidazoline,thiazoline, and the like.

The term “monocyclic 4- to 8-membered non-aromatic heterocyclic group”as used throughout the present specification refers to a monovalent ordivalent group derived by removing 1 or 2 hydrogen atoms from anydesired position of the aforementioned “monocyclic 4- to 8-memberednon-aromatic heterocycle”.

The term “bicyclic 6- to 12-membered hydrocarbon ring” as usedthroughout the present specification refers to a bicyclic hydrocarbonring having 6 to 12 carbons composing the ring, and specific examplesthereof include

-   (1) hydrocarbon rings represented by the formula:

(wherein M^(1a), M^(2a), M^(3a) each independently represent—(CH₂)_(m1)— (wherein m¹ is an integer of 0 to 2), with the proviso thatM^(1a), M^(2a) and M^(3a) are not all —(CH₂)₀—),

-   (2) hydrocarbon rings represented by the formula:

(wherein M^(6a) represents —(CH₂)_(m3)— (wherein m3 is an integer of 0to 3)), and

-   (3) hydrocarbon rings represented by the formula:

(wherein M^(4a), M^(5a) each independently represent —(CH₂)_(m2)—(wherein m2 is an integer of 0 to 3)).

As specific examples of such a “bicyclic 6- to 12-membered hydrocarbonring” there may be mentioned bicyclo[3.1.0]hexane,bicyclo[4.1.0]heptane, spiro[2.4]heptane, spiro[2.5]octane,bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane, bicyclo[3.3.1]nonane,bicyclo[3.2.1]octane, spiro[4.5]decane, spiro[3.5]nonane, norbornane,bicyclo[2.1.0]pentane, bicyclo[3.3.0]octane, bicyclo[2.2.2]octane,bicyclo[3.3.3]undecane, and the like.

As preferred examples of the “bicyclic 6- to 12-membered hydrocarbonring” there may be mentioned bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane,bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, spiro[4.5]decane,spiro[3.5]nonane, bicyclo[3.3.0]octane, and the like.

The term “bicyclic 6- to 12-membered non-aromatic heterocycle” as usedthroughout the present specification refers to

-   (1) a bicyclic non-aromatic ring,-   (2) having 6 to 12 atoms in the ring,-   (3) containing 1 to 3 hetero atoms among the atoms of the ring,-   (4) optionally including 1 double bond in the ring, and-   (5) optionally including 1 to 3 carbonyl groups in the ring.

That is, a “bicyclic 6- to 12-membered non-aromatic heterocycle” is aring formed by replacing any 1 to 3 methine or methylene groups in thering of the aforementioned “bicyclic 6- to 12-membered hydrocarbon ring”with oxygen, sulfur, nitrogen or —NH—.

The term “bicyclic 6- to 12-membered non-aromatic heterocyclic group” asused throughout the present specification refers to a divalent groupderived by removing any 2 hydrogen atoms from the aforementioned“bicyclic 6- to 12-membered non-aromatic heterocycle”.

The term “monocyclic or bicyclic 4- to 12-membered non-aromaticheterocyclic group” as used throughout the present specification refersto the aforementioned “monocyclic 4- to 8-membered non-aromaticheterocyclic group” or the aforementioned “bicyclic 6- to 12-memberednon-aromatic heterocyclic group”.

The term “monocyclic 5- to 7-membered carbon ring” as used throughoutthe present specification refers to

-   (1) a monocyclic ring,-   (2) having 5 to 7 atoms in the ring,-   (3) wherein all of the atoms of the ring are carbon atoms,-   (4) optionally including 1 or 2 double bonds in the ring, and-   (5) optionally including 1 to 3 carbonyl groups in the ring.

As specific examples of monocyclic 5- to 7-membered carbon rings theremay be mentioned cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, cyclopentanone or cyclohexanone, and the like.

The term “9- to 11-membered benzene fused ring” as used throughout thepresent specification refers to a ring composed of 9 to 11 atoms, formedby fusing a 5- to 7-membered non-aromatic heterocycle or monocyclic 5-to 7-membered carbon ring with benzene. Here, a “5- to 7-memberednon-aromatic heterocycle” refers to the “monocyclic 4- to 8-memberednon-aromatic heterocycle” mentioned above which has 5 to 7 atomscomposing the ring.

Specific examples of 9- to 11-membered benzene fused rings include ringsrepresented by the formula:

(wherein

 represents a single bond or a double bond, and Y¹, Y², Y³, Y⁴ and Y⁵each independently represent carbonyl, oxygen, sulfur, nitrogen,methylene, methine or —NR³⁴— (wherein R³⁴ represents hydrogen or C₁₋₆alkyl)), preferably rings represented by the formula:

(wherein Y¹, Y², Y³, Y⁴ and Y⁵ each represent carbonyl, oxygen, sulfur,methylene or —NR³⁴— (wherein R³⁴ represents hydrogen or C₁₋₆ alkyl)),and more preferably rings represented by the formula:

(wherein Y¹, Y², Y³ and Y⁴ have the same respective definitions asabove).

The term “9 to 11-membered benzene fused ring group” as used throughoutthe present specification refers to a monovalent group derived byremoving 1 hydrogen atom from any desired position of the aforementioned“9- to 11-membered benzene-fused ring”.

The term “9- to 11-membered aromatic heterocycle-fused ring” as usedthroughout the present specification refers to a bicyclic ring composedof 9 to 11 atoms, formed by fusing the aforementioned “5- to 7-memberednon-aromatic heterocycle” or “monocyclic 5- to 7-membered carbon ring”with a “5- to 6-membered aromatic heterocycle” such as pyridine,thiophene, furan or the like.

The term “9- to 11-membered aromatic heterocycle fused ring group” asused throughout the present specification refers to a monovalent groupderived by removing 1 hydrogen atom from any desired position of theaforementioned “9- to 11-membered aromatic heterocycle fused ring”.

The term “5-membered heterocycle containing —C(=Q¹)- and a nitrogenatom” as used throughout the present specification refers to a ringrepresented by the formula:

(wherein Q¹ has the same definition as above, T⁶ and T⁸ eachindependently represent methine or nitrogen, T⁷ represents methylene,oxygen, sulfur or —NR²⁰—, and R²⁰ and R²¹ each independently representhydrogen or C₁₋₆ alkyl), and preferably a ring represented by theformula:

(wherein Q¹, T⁷, R²⁰ and R²¹ have the same respective definitions asabove).

The term “6-membered heterocycle containing —C(=Q¹)- and a nitrogenatom” as used throughout the present specification refers to a ringrepresented by the formula:

(wherein Q¹ has the same definition as above, T¹, T², T³ and T⁴ eachindependently represent methine or nitrogen, and R²¹ represents hydrogenor C₁₋₆ alkyl), preferably a ring represented by the formula:

(wherein Q¹ and R²¹ have the same respective definitions as above), morepreferably a ring represented by the formula:

(wherein Q¹ and R²¹ have the same respective definitions as above), andeven more preferably a ring represented by the formula:

The term “7-membered heterocycle containing —C(=Q¹)- and a nitrogenatom” as used throughout the present specification refers to a ringrepresented by the formula:

(wherein Q¹, R²⁰ and R²¹ have the same definitions as above, T⁶, T⁸, T⁹and T¹⁰ each independently represent methine or nitrogen, and T⁷represents methylene, oxygen, sulfur or —NR²⁰—).

The term “5-membered heterocyclic group containing —C(=Q¹)- and anitrogen atom” as used throughout the present specification refers to amonovalent group derived by removing 1 hydrogen atom from any desiredposition of the aforementioned “5-membered heterocycle containing—C(=Q¹)- and a nitrogen atom”.

The term “6-membered heterocyclic group containing —C(=Q¹)- and anitrogen atom” as used throughout the present specification refers to amonovalent group derived by removing 1 hydrogen atom from any desiredposition of the aforementioned “6-membered heterocycle containing—C(=Q¹)- and a nitrogen atom”.

The term “7-membered heterocyclic group containing —C(=Q¹)- and anitrogen atom” as used throughout the present specification refers to amonovalent group derived by removing 1 hydrogen atom from any desiredposition of the aforementioned “7-membered heterocycle containing—C(=Q¹)- and a nitrogen atom”.

The term “5- to 7-membered heterocyclic group containing —C(=Q¹)- and anitrogen atom” as used throughout the present specification refers to acyclic group having 5 to 7 atoms composing the ring of the cyclic group,containing —(C=Q¹)- in the ring, and including 1 to 5 hetero atoms amongthe atoms composing the ring of the cyclic group, and such a group isthe aforementioned “5-membered heterocyclic group containing —C(=Q¹)-and a nitrogen atom”, “6-membered heterocyclic group containing —C(=Q¹)-and a nitrogen atom” or “7-membered heterocyclic group containing—C(=Q¹)- and a nitrogen atom”.

The formula:

as used throughout the present specification refers to a grouprepresented by the formula:

(wherein Q¹ and R²¹ have the same definitions as above), and preferablya group represented by the formula:

(wherein Q¹ and R²¹ have the same definitions as above).

The formula:

as used throughout the present specification refers to a grouprepresented by the formula:

(wherein Q¹, R¹ and u have the same respective definitions as above),and preferably a group represented by the formula:

(wherein Q¹, R²¹ and u have the same respective definitions as above).

The phrase “5- to 10-membered aromatic heterocyclic group having atleast one group selected from the group consisting of optionallysubstituted C₁₋₆ alkoxy groups, C₁₋₆ alkylthio groups, hydroxyl,mercapto and —NR¹³R¹⁴ (wherein R¹³ and R¹⁴ each independently representhydrogen or C₁₋₆ alkyl), and also having other optional substituents” asused throughout the present specification refers to the aforementioned“5- to 10-membered aromatic heterocyclic group” having at least onegroup selected from the group consisting of optionally substituted C₁₋₆alkoxy groups, C₁₋₆ alkylthio groups, hydroxyl, mercapto and —NR¹³R¹⁴(wherein R¹³ and R¹⁴ each independently represent hydrogen or C₁₋₆alkyl).

Specifically, this refers to a monovalent group derived by removing 1hydrogen atom from any desired position of a ring represented by theformula:

(wherein T¹, T², T³, T⁴, T⁶, T⁷, T⁸, T⁹ and T¹⁰ have the same respectivedefinitions as above, and Q² represents optionally substituted C₁₋₆alkoxy, C₁₋₆ alkylthio, hydroxyl, mercapto or —NR¹³R¹⁴ (wherein R¹³ andR¹⁴ represent hydrogen or C₁₋₆ alkyl)), preferably a monovalent groupderived by removing 1 hydrogen atom from any desired position of a ringrepresented by the formula:

(wherein Q² has the same definition as above), more preferably amonovalent group derived by removing 1 hydrogen atom from any desiredposition of a ring represented by the formula:

(wherein Q² has the same definition as above), and even more preferablya monovalent group derived by removing 1 hydrogen atom from any desiredposition of a ring represented by the formula:

(wherein Q² has the same definition as above).

The term “piperidine-diyl” as used throughout the present specificationrefers to a divalent group derived by removing 2 hydrogen atoms from anydesired positions of piperidine, and specific examples include groupsrepresented by the formula:

The term “azetidine-diyl” as used throughout the present specificationrefers to a divalent group derived by removing 2 hydrogen atoms from anydesired positions of azetidine.

The term “pyrrolidine-diyl” as used throughout the present specificationrefers to a divalent group derived by removing 2 hydrogen atoms from anydesired positions of pyrrolidine.

The term “azepane-diyl” as used throughout the present specificationrefers to a divalent group derived by removing 2 hydrogen atoms from anydesired positions of azepane.

The term “piperazine-diyl” as used throughout the present specificationrefers to a divalent group derived by removing 2 hydrogen atoms from anydesired positions of piperazine.

The phrase “phenyl-C₁₋₆ alkyl group optionally having 1 to 3substituents selected from the group consisting of hydroxyl, C₁₋₆alkoxy, C₁₋₆ alkyl, amino, halogen and cyano” as used throughout thepresent specification refers to phenyl-bonded C₁₋₆ alkyl groupsoptionally having 1 to 3 substituents selected from the group consistingof hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, amino, halogen and cyano.

The phrase “phenyloxy-C₁₋₆ alkyl group optionally having 1 to 3substituents selected from the group consisting of hydroxyl, C₁₋₆alkoxy, C₁₋₆ alkyl, amino, halogen and cyano” as used throughout thepresent specification refers to phenyloxy-bonded C₁₋₆ alkyl groupsoptionally having 1 to 3 substituents selected from the group consistingof hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, amino, halogen and cyano.

The phrase “General formula (I):

wherein Z¹ is a group represented by the formula:

as used throughout the present specification means that general formula(I) is represented by the formula:

and preferably by the formula:

The phrase “General formula (I):

wherein Z¹ is a group represented by the formula:

as used throughout the present specification means that formula (I) isrepresented by the formula:

and preferably by the formula:

The term “optionally having . . . substituents” as used throughout thepresent specification means that the group may have one or moresubstituents in any desired combination at substitutable positions. Asspecific examples of such substituents there may be mentioned thefollowing:

-   (1) halogen,-   (2) hydroxyl,-   (3) thiol,-   (4) nitro,-   (5) cyano,-   (6) formyl,-   (7) carboxyl,-   (8) trifluoromethyl,-   (9) trifluoromethoxy,-   (10) amino, and-   (11) -T^(1x)-T^(2x) (wherein T^(1x) represents a single bond, C₁₋₆    alkylene, oxygen, —CO—, —S—, —S(O)—, —S(O)₂—, —CO—, —CO—O—,    —NR^(T)—, —CO—NR^(T)—, —NR^(T)—CO—, —SO₂—NR^(T)—, —NR^(T)—SO₂—,    —NH—CO—NR^(T)— or —NH—CS—NR^(T)—,    T^(2x) represents hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, phenyl, 1-naphthyl, 2-naphthyl, a 5- to    10-membered aromatic heterocyclic group or a monocyclic 4- to    8-membered non-aromatic heterocyclic group, and    R^(T) represents hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl    or C₂₋₆ alkynyl,    with the proviso that T^(2x) and R^(T) may each independently have 1    to 3 groups selected from Substituent Group T below.    <Substituent Group T>    The group consisting of hydroxyl, cyano, halogen, C₁₋₆ alkyl, C₃₋₈    cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, 1-naphthyl,    2-naphthyl, a 5- to 10-membered aromatic heterocyclic group, a    monocyclic 4- to 8-membered non-aromatic heterocyclic group, C₁₋₆    alkoxy, C₁₋₆ alkylthio, C₂₋₇ alkoxycarbonyl, etc.

The term “salt” as used throughout the present specification is notparticularly restrictive so long as it is a salt of the compound of theinvention and pharmacologically acceptable, and examples thereof includean inorganic acid salt, an organic acid salt, an inorganic base salt, anorganic base salt, and an acidic or basic amino acid salt.

As preferred examples of an inorganic acid salt there may be mentionedhydrochloride, hydrobromide, sulfate, nitrate and phosphate, and aspreferred examples of organic acid salts there may be mentioned acetate,succinate, fumarate, maleate, tartrate, citrate, lactate, stearate,benzoate, methanesulfonate and p-toluenesulfonate.

As preferred examples of an inorganic base salt there may be mentionedan alkaline metal salt such as a sodium salt and a potassium salt, analkaline earth metal salt such as a calcium salt and a magnesium salt,an aluminium salt and an ammonium salt, and as preferred examples of anorganic base salt there may be mentioned a diethylamine salt, adiethanolamine salt, a meglumine slat and a N,N′-dibenzylethylenediaminesalt.

As preferred examples of an acidic amino acid salt there may bementioned aspartate and glutamate, and as preferred examples of a basicamino acid salt there may be mentioned an arginine salt, a lysine saltand an ornithine salt.

Representative production schemes for compounds represented by generalformula (I) above according to the invention will now be presented.

In the following production schemes, 1 represents an integer of 0 to 2,m represents an integer of 0 to 2, n represents an integer of 0 to 4, prepresents an integer of 0 to 3, q represents an integer of 0 to 3, andr represents an integer of 0 to 2.

Met^(x1) represents lithium, sodium, potassium, —Mg—Br, etc., Met^(x2)represents —Zn—R, —SnR₃, —B(OR)₂ (wherein R represents C₁₋₆ alkyl,etc.), etc., and Met^(x3) represents lithium, sodium, potassium, cesium,etc.

R^(x1) represents tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, etc.,R represents C₁₋₆ alkyl, etc., R^(x2), R^(x20), R^(x21), R^(x22) eachrepresent hydrogen or C₁₋₆ alkyl, R^(x3) represents hydrogen, halogen,nitrile, C₁₋₆ alkyl, C₁₋₆ alkoxy, etc., R^(x4) represents C₁₋₆ alkyl,benzyl, p-methoxybenzyl, etc., and R^(x5) represents C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, etc.

Ts represents p-toluenesulfonyl.

L^(x1) represents a leaving group such as halogen, methanesulfonyloxy,trifluoromethanesulfonyloxy, para-toluenesulfonyloxy, etc., L^(x2)represents halogen, trifluoromethanesulfonyloxy, etc. and L^(x3)represents chlorine or bromine.

V^(1x) represents oxygen, sulfur, nitrogen or —NR— (wherein R has thesame definition as above).

X represents halogen.

A¹, A², X¹, X², X³, X⁴, Q¹, T¹, Z¹ and s have the same definitions asabove.

The “room temperature” referred to below is in the range of 15-30° C.

wherein (d-36) has the same definition as Z¹ above.Step A-1

A step of obtaining compound (a-2) by reductive amination of compound(a-1) and compound (d-35).

The reaction may be conducted under the same conditions commonlyemployed for reductive amination with carbonyl compounds and aminecompounds. There are no particular restrictions on the reductionreaction, and there may be mentioned reductive amination using areducing agent such as borane, borohydride complex, formic acid or thelike, and catalytic reduction using a metal catalyst under a hydrogenatmosphere.

As examples of reductive amination using a borohydride complex there maybe mentioned the processes described in W. S. Emerson, OrganicReactions, 4, 174 (1948), C. F. Lane, Synthesis, 135 (1975), J. C.Stowell and S. J. Pedegimas, Synthesis, 127 (1974), A. F. Abdel-Magid,K. G. Carson, B. D. Harris, C. A. Maryanoff and R. D. Shah, Journal ofOrganic Chemistry, 61, 3849 (1996) and elsewhere.

Compound (d-35) may be free or in the form of a salt, and preferably ahydrochloride or a hydrobromide of compound (d-35) is used.

Sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride or the like may be used as the borohydridecomplex.

When a borohydride complex is used as the reducing agent, there are noparticular restrictions on the solvent so long as it does not inhibitthe reaction and dissolves the starting substances to some extent, andspecifically there may be used, for example, methanol, ethanol,tetrahydrofuran, dichloromethane and 1,2-dichloroethane. The reactionmay be conducted in the copresence of an acid to achieve more favorableresults such as increased yield. There are no particular restrictions onsuch an acid, and there may be mentioned mineral acids such ashydrochloric acid, organic acids such as acetic acid, and Lewis acidssuch as zinc chloride, boron trifluoride diethyl ether complex andtitanium (IV) tetraisopropoxide. The reaction temperature is notparticularly restricted but will normally be from −78° C. to the refluxtemperature of the solvent, and is preferably from freezing to roomtemperature.

When formic acid is used as the reducing agent, there are no particularrestrictions on the solvent so long as it does not inhibit the reaction,and an excess of formic acid may be used as the solvent. The reactiontemperature is not particularly restricted but will normally be from 50°C. to the reflux temperature of the solvent. High-temperature heating at150-250° C. in a hermetic pressure-resistant vessel may providefavorable results such as shortening of the reaction time.

The solvent used for catalytic reduction under a hydrogen atmosphere isnot particularly restricted so long as it does not inhibit the reaction,and there may be mentioned methanol, ethanol, tetrahydrofuran and1,4-dioxane. The metal catalyst used for the reaction may bepalladium-carbon, platinum oxide, Raney nickel or the like. Theconditions for the reaction are not particularly restricted, and it maybe carried out from room temperature to the reflux temperature of thesolvent and from ordinary pressure to 150 atmospheres, and preferablyfrom room temperature to 60° C. and from ordinary pressure to 5atmospheres.

Step A-2

A step of obtaining compound (a-4) by Michael addition reaction ofcompound (a-3) and compound (d-35).

The reaction may be conducted under the same conditions commonlyemployed for Michael addition reaction with an olefin compound and anamine compound.

For example, the reaction may be conducted under the same conditionsdescribed in W. E. Doering and R. A. N. Weil, Journal of the AmericanChemical Society, 69, 2461 (1947), M.-C. Viaud, P. Jamoneau, L. Savelonand G. Guillaumet, Tetrahedron Letters, 37, 2409 (1996).

Compound (d-35) may be free or in the form of a salt.

There are no particular restrictions on the solvent so long as it doesnot inhibit the reaction, and as preferred solvents there may bementioned methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, toluene,xylene and acetic acid. The reaction temperature will differ dependingon the starting materials and solvent used and is not particularlyrestricted, but it is preferably from room temperature to the refluxtemperature of the solvent. The reaction may be carried out withaddition of an acid such as p-toluenesulfonic acid or camphorsulfonicacid or alumina, as this may provide favorable results such asshortening of the reaction time and increased yield.

High-temperature heating at 150-250° C. in a hermetic pressure-resistantvessel may also provide favorable results such as shortening of thereaction time.

Step A-3

A step of obtaining compound (a-6) by nucleophilic substitution reactionof compound (a-5) and compound (d-35).

The reaction may be conducted under the same conditions commonlyemployed for reaction between a halogenated compound and a nucleophilicreagent (for example, the conditions described in H. Arai, T. Ashizawa,K. Gomi, M. Kono, H. Saito and M. Kasai, Journal of Medicinal Chemistry,38, 3025 (1995)).

Compound (d-35) may be free or in the form of a salt.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and as preferred solvents there maybe mentioned methanol, ethanol, propanol, tetrahydrofuran, benzene,toluene, xylene, acetonitrile, dichloromethane, chloroform,N,N-dimethylformamide and dimethylsulfoxide. The reaction temperaturewill normally be from room temperature to the reflux temperature of thesolvent, and preferably from room temperature to 100° C. Addition of abase may provide favorable results such as increased yield. The baseused is not particularly restricted so long as it does not inhibit thereaction, and as preferred bases there may be mentioned sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,diazabicycloundecene, sodium hydride, potassium hydride, sodiummethoxide, potassium methoxide, potassium tert-butoxide anddiisopropylethylamine.

Step B-1

A step of obtaining compound (b-2) by oxidation of compound (b-1).

The reaction may be carried out under the same reaction conditionscommonly employed for oxidation to obtain a sulfoxide compound orsulfone compound from a sulfide compound (for example, the conditionsdescribed in G. A. Russel and L. A. Ochrymowycz, Journal of OrganicChemistry, 35, 2106 (1970)).

The oxidizing agent used may be m-chloroperbenzoic acid, hydrogenperoxide, peracetic acid or the like. There are no particularrestrictions on the solvent used for the reaction so long as it does notinhibit the reaction and dissolves the starting substances to someextent, and for example, dichloromethane and chloroform are preferred.The reaction temperature is not particularly restricted but willnormally be from −78° C. to room temperature. Addition of a base mayprovide favorable results such as increased yield. The base used is notparticularly restricted so long as it does not inhibit the reaction, andas preferred bases there may be mentioned sodium carbonate, sodiumbicarbonate, potassium carbonate and the like.

Step B-2

A step of obtaining compound (b-4) by reduction of compound (b-3).

Sodium borohydride, lithium borohydride, lithium aluminium hydride, zincborohydride or the like may be used as the reducing agent.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and specifically there may be usedmethanol, ethanol, tetrahydrofuran and the like.

The reaction temperature is not particularly restricted but willnormally be from −78° C. to the reflux temperature of the solvent, andpreferably from freezing to room temperature.

Step B-3

A step of obtaining compound (b-7) by reacting compound (b-5) with(b-6).

The reaction may be conducted under the same reaction conditionsdescribed, for example, in A. Aranda, A. Diaz, E. Diez-Barra, A. De laHoz, A. Moreno and P. Sanchez-Verdu, Journal of the Chemical Society:Perkin Transactions I, 2427 (1992).

Specifically, for example, a base is reacted with a solution of compound(b-5) to form an anion, which is then reacted with compound (b-6) toobtain compound (b-7).

There are no particular restrictions on the solvent used so long as itdoes not inhibit the reaction, and from 1 equivalent to a large excessof an appropriate base may be used in an organic solvent such as diethylether, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or the like.As bases to be used there may be mentioned potassium hydride, sodiumhydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide andlithium diisopropylamide.

Conducting the reaction in the copresence of an ammonium salt such astetra-n-butylammonium chloride, tetra-n-butylammonium bromide ortetra-n-butylammonium iodide may provide favorable results such asincreased yield and shortening of the reaction time.

The reaction temperature is not particularly restricted but willnormally be from −78° C. to room temperature.

Step B-4

A step of obtaining compound (b-10) by condensation of compound (b-8)with compound (b-9).

The reaction may be conducted under the same reaction conditionsdescribed, for example, in P. R. Dave, M. Ferraro, H. L. Ammon and C. S.Choi, Journal of Organic Chemistry, 55, 4459 (1990).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and specifically there may be usedmethanol, ethanol, propanol, pyridine or the like. Compound (b-9) may befree or in the form of a salt, and preferably a hydrochloride orhydrobromide of compound (b-9) is used. The reaction temperature is notparticularly restricted but will normally be from freezing to the refluxtemperature of the solvent, and is preferably from room temperature tothe reflux temperature of the solvent. Addition of a base may providefavorable results such as increased yield. The base used is notparticularly restricted so long as it does not inhibit the reaction, andas preferred bases there may be mentioned sodium carbonate, potassiumcarbonate, sodium acetate and potassium acetate.

Step C-1

A step of obtaining compound (c-2) by reacting compound (c-1) with anacid.

The reaction may be conducted under the same conditions described in,for example, A. C. Rasmussen and D. A. Rawlings, Eur. Journal ofMedicinal Chemistry, 28, 601-608 (1993), F. G. Fang, S. Xie and M. W.Lowery, Journal of Organic Chemistry, 59, 6142 (1994).

Specifically, for example, compound (c-1) may be dissolved in 5Nhydrochloric acid or the like and heated to reflux to obtain compound(c-2).

The reaction may be conducted without a solvent or in water, in amixture of water and an organic solvent such as methanol, ethanol,tetrahydrofuran or 1,4-dioxane, or in an organic solvent such asmethanol, ethanol, tetrahydrofuran, 1,4-dioxane or ethyl acetate, withaddition of from 1 equivalent to a large excess of an appropriate acid.The acid used is preferably, for example, hydrogen chloride,hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid,trifluoroacetic acid or the like, and thionyl chloride may also be addedto an alcohol solvent to generate an acid in the reaction system.

The reaction temperature will normally be from freezing to the refluxtemperature of the solvent.

The reaction may be carried out with addition of from 1 equivalent to alarge excess of iodotrimethylsilane or chlorotrimethylsilane-sodiumiodide instead of an acid. There are no particular restrictions on thereaction solvent so long as it does not inhibit the reaction, and theremay be used dichloromethane, chloroform, acetonitrile or the like.

The reaction temperature will normally be from −78° C. to the refluxtemperature of the solvent, and it is preferably from −20° C. to roomtemperature.

The reaction may also be carried out with addition of from 1 equivalentto a large excess of boron tribromide or boron trichloride instead of anacid. There are no particular restrictions on the reaction solvent solong as it does not inhibit the reaction, and there may be useddichloromethane, chloroform, 1,2-dichloroethane or the like.

The reaction temperature will normally be from −78° C. to the refluxtemperature of the solvent, and it is preferably from −78° C. to roomtemperature.

Step C-2

A step of obtaining compound (c-4) by reacting compound (c-2) withcompound (c-3).

The reaction may be conducted under the same conditions described in,for example, J. B. Press and J. J. Mcnally, Journal of HeterocyclicChemistry, 25, 1571 (1988).

As a specific example, a base may be reacted with a solution of compound(c-2) to form an anion, which is then reacted with compound (c-3) toobtain compound (c-4).

There are no particular restrictions on the solvent used so long as itdoes not inhibit the reaction, and the reaction may be conducted withfrom 1 equivalent to a large excess of an appropriate base in an organicsolvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane orN,N-dimethylformamide. As bases to be used there may be mentioned sodiumhydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide,sodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, triethylamine, diisopropylethylamine and the like.

The reaction temperature will normally be from freezing to the refluxtemperature of the solvent.

The following is a representative synthesis scheme for a compound to beused in Step A above.

wherein (d-36) has the same definition as Z¹ above.Step D-1

A step of obtaining compound (d-2) by reacting compound (d-1) with anorganometallic reagent (d-4).

The reaction may be carried out under the same conditions commonly usedfor nucleophilic addition reaction whereby an aldehyde compound and anorganometallic reagent are reacted to obtain an alcohol compound (forexample, J. C. H. Hwa and H. Sims, Organic Synthesis, V, 608 (1973), C.Z. DING, Synthetic Communication, 26, 4267 (1996).

Specifically, the reaction may be conducted by adding a solution ofcompound (d-4) dropwise to a solution of compound (d-1), or conversely,by adding a solution of compound (d-1) dropwise to a solution ofcompound (d-4).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and specifically there may be useddiethyl ether, tetrahydrofuran, 1,4-dioxane and the like. The reactiontemperature is not particularly restricted, but the reaction may usuallybe conducted from −78° C. to room temperature. The organometallicreagent (d-4) will generally be used in the reaction at 1-5 equivalentswith respect to compound (d-1).

Step D-2

A step of obtaining compound (d-3) by oxidation of compound (d-2).

The reaction may be carried out under the same conditions commonlyemployed for oxidation of a secondary alcohol compound to a ketonecompound (for example, the conditions described in A. J. Mancuso and D.Swern, Synthesis, 165 (1981)).

The oxidation method to be used for the oxidation reaction may be Swernoxidation, Jones oxidation, Corey Kim oxidation or the like. Theoxidizing agent used for the oxidation may be an alkylsulfoniumylideprepared from dimethylsulfoxide-oxalyl chloride and the like, Jones'reagent, pyridinium chlorochromate, pyridinium dichromate or sulfurtrioxide-pyridine complex.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and examples which may be usedinclude dimethylsulfoxide, acetone, dichloromethane and chloroform. Thereaction temperature is not particularly restricted, but the reactionmay usually be conducted from −78° C. to room temperature.

Step D-3

A step of obtaining compound (d-3) by reacting compound (d-5) with anorganometallic reagent (d-4).

The reaction may be carried out under the same conditions commonlyemployed for addition reaction whereby a cyano compound and anorganometallic reagent are reacted to obtain a ketone compound (forexample, the conditions described in R. B. Moffet and R. L. Schriner,Organic Synthesis, II, 562 (1955)).

The reaction conditions including the reagent equivalents, the solventand the temperature for the reaction are the same as in Step D-1 above.

Step D-4

A step of obtaining compound (d-3) by reacting compound (d-6) with anorganometallic reagent (d-4).

The reaction may be carried out under the same conditions commonlyemployed for reaction of an amide compound and an organometallic reagentto obtain a ketone compound (for example, the conditions described in S.Nahm and S. M. Weinreb, Tetrahedron Letters, 22, 3825 (1981)).

The reaction conditions including the reagent equivalents, the solventand the temperature for the reaction are the same as in Step D-1 above.

Step D-5

A step of obtaining an organometallic reagent (d-4) from compound (d-7).

The reaction may be carried out under the same conditions commonlyemployed for reaction of a halogenated compound with an alkyllithiumreagent such as n-butyllithium or sec-butyllithium, or magnesium, toobtain an organometallic reagent (for example, J. C. H. Hwa and H. Sims,Organic Synthesis, V, 608 (1973), C. Z. DING, Synthetic Communication,26, 4267 (1996)).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and preferred examples includediethyl ether, tetrahydrofuran and 1,4-dioxane. The reaction temperatureis not particularly restricted but will normally be from −78° C. to thereflux temperature of the solvent.

Step D-6

A step of obtaining compound (d-3a) by reacting compound (d-1) andcompound (d-8) in the presence of a base. The reaction may be carriedout under the same conditions described in, for example, S. R. Angel andM. L. Neitzel; Journal of Organic Chemistry, 65, 6485 (2000).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, but methanol, ethanol,ethyleneglycol, formamide and the like are preferred. The base used ispreferably, for example, sodium hydroxide, sodium methoxide, sodiumethoxide or potassium methoxide. The base is used at 1-5 equivalentswith respect to the starting material. The reaction temperature is notparticularly restricted but will normally be from room temperature to100° C.

(wherein (d-36) has the same definition as Z¹ above).Step D-7

A step of obtaining compound (d-11) by Mitsunobu reaction with compound(d-9) and compound (d-10).

The reaction may be carried out under the same conditions commonlyemployed for Mitsunobu reaction (for example, the conditions describedin O. Mitsunobu, Synthesis, 1 (1981), D. L. Hughes, Organic Reactions,42, 335 (1992)).

The reaction is conducted using a phosphine derivative such astriphenylphosphine and an azodicarboxylic acid diester such as diethylazodicarboxylate. There are no particular restrictions on the solventused for the reaction so long as it does not inhibit the reaction anddissolves the starting substances to some extent, and for example, theremay be used tetrahydrofuran, benzene, toluene or the like. The reactiontemperature is not particularly restricted, but will usually be fromfreezing to room temperature.

Step D-8

A step of obtaining compound (d-12) by converting the hydroxyl group ofcompound (d-9) to a leaving group.

As leaving groups there may be mentioned halogen (chlorine, bromine andiodine), and sulfonyloxy groups such as methanesulfonyloxy,p-toluenesulfonyloxy and trifluoromethanesulfonyloxy.

The reaction may be carried out under the same conditions commonlyemployed for conversion of a hydroxyl group to a leaving group (forexample, the reaction conditions described in R. K. Crossland and K. L.Servis, Journal of Organic Chemistry, 35, 3195 (1970)).

When the leaving group is halogen, compound (d-12) may be produced byreacting compound (d-9) with thionyl chloride, thionyl bromide,phosphorus tribromide or tetrahalogenomethane-triphenylphosphine. Thereare no particular restrictions on the solvent used for the reaction solong as it does not inhibit the reaction and dissolves the startingsubstances to some extent, and as preferred solvents there may bementioned benzene, toluene, xylene, dichloromethane and chloroform. Thereaction temperature will normally be from −78° C. to the refluxtemperature of the solvent, and is preferably from freezing to thereflux temperature of the solvent.

When the leaving group is a sulfonyloxy group, compound (d-12) may beproduced by reacting compound (d-9) with methanesulfonyl chloride,p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride or thelike. There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and as preferred solvents there maybe mentioned tetrahydrofuran, toluene, xylene, dichloromethane,chloroform and N,N-dimethylformamide. The reaction temperature willnormally be from −78° C. to the reflux temperature of the solvent, andis preferably from freezing to room temperature. Addition of a base mayprovide favorable results such as increased yield. The base used is notparticularly restricted so long as it does not inhibit the reaction, andas preferred bases there may be mentioned sodium carbonate, potassiumcarbonate, triethylamine, pyridine and diisopropylethylamine.

Step D-9

A step of obtaining compound (d-11) by reacting compound (d-12) withcompound (d-13).

The reaction may be carried out under the same conditions commonlyemployed for reaction between a halogenated compound and a nucleophilicreagent (for example, the conditions described in H. Arai, T. Ashizawa,K. Gomi, M. Kono, H. Saito and M. Kasai, Journal of Medicinal Chemistry,38, 3025 (1995)).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and as preferred solvents there maybe mentioned methanol, ethanol, propanol, tetrahydrofuran, benzene,toluene, xylene, acetonitrile, dichloromethane, chloroform,N,N-dimethylformamide and dimethylsulfoxide. The reaction temperaturewill normally be from room temperature to the reflux temperature of thesolvent, and is preferably from room temperature to 150° C. Addition ofa base may provide favorable results such as increased yield. The baseused is not particularly restricted so long as it does not inhibit thereaction, and as preferred bases there may be mentioned sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,diazabicycloundecene, sodium hydride, potassium hydride, sodiummethoxide, potassium methoxide, potassium tert-butoxide anddiisopropylethylamine.

Step D-10

A step of obtaining compound (d-16) by reacting compound (d-14) withcompound (d-15).

The reaction may be carried out under the same conditions commonlyemployed for reaction between a halogenated compound and a nucleophilicreagent (for example, the conditions described in E. Montenegro, R.Echarri, C. Clayer, S. Castillon, A. Moyano, M. A. Pericas, A. Riera,Tetrahedron: Asymmetry, 7, 3553 (1996)).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and as preferred solvents there maybe mentioned methanol, ethanol, propanol, tetrahydrofuran, benzene,toluene, xylene, acetonitrile, dichloromethane, chloroform,N,N-dimethylformamide and dimethylsulfoxide. The reaction temperaturewill normally be from room temperature to the reflux temperature of thesolvent, and is preferably from room temperature to 100° C. Addition ofa base may provide favorable results such as increased yield. The baseused is not particularly restricted so long as it does not inhibit thereaction, and as preferred bases there may be mentioned sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,diazabicycloundecene, sodium hydride, potassium hydride, sodiummethoxide, potassium methoxide, potassium tert-butoxide anddiisopropylethylamine.

(wherein (d-37) represents a monocyclic 4- to 8-membered non-aromaticheterocycle containing a carbonyl group, such as oxoazetidin-1-yl,oxopyrrolidin-1-yl, oxopiperidin-1-yl, oxoazocan-1-yl, etc.)Step D-11-1

A step of obtaining compound (d-18) by reacting compound (d-17) with acarbon tetrahalide such as carbon tetrabromide, and triphenylphosphine.

The reaction may be carried out under the same conditions described in,for example, E. J. Corey and P. L. Fuchs, Tetrahedron Letters, 3769(1972).

Specifically, compound (d-18) may be obtained, for example, by addingtriphenylphosphine to a solution of carbon tetrabromide, stirring themixture for several minutes to several hours, and then adding a solutionof compound (d-17) dropwise and further stirring for several hours to 1day.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and for example, there may be useddichloromethane, chloroform, 1,2-dichloroethane and the like. Thereaction temperature is not particularly restricted but will normally befrom −78° C. to 100° C., and is preferably from −10° C. to roomtemperature.

The reaction may also be carried out in the presence of zinc.

Step D-11-2

A step of obtaining compound (d-20) by reacting compound (d-18) with abase for dehalogenation to convert it to an alkynyl metal derivative,and then reacting this with compound (d-19).

The reaction may be carried out under the same conditions described in,for example, E. J. Corey and P. L. Fuchs, Tetrahedron Letters, 3769(1972).

Specifically, compound (d-20) may be obtained, for example, by adding asolution of the base dropwise to a solution of compound (d-18), stirringthe mixture for several minutes to several hours, and then adding asolution of compound (d-19) dropwise and further stirring for severalminutes to several hours.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and examples of preferred solventsinclude diethyl ether, tetrahydrofuran. 1,4-dioxane and the like. Asexamples of bases to be used there may be mentioned n-butyllithium,sec-butyllithium and tert-butyllithium. The base is usually used at 2-5equivalents with respect to the starting material. The reactiontemperature is not particularly restricted but will normally be from−78° C. to room temperature.

(wherein (d-36) has the same definition as Z¹ above).Step D-12

A step of obtaining compound (d-22) by oxidation of compound (d-21).

The reaction may be carried out under the same conditions as for StepB-1.

Step D-13

A step of obtaining compound (d-25) by reacting compound (d-23) withcompound (d-24).

The reaction may be carried out under the same conditions as for StepB-3.

When Z¹ is a piperidine-diyl group, the synthesis may also be carriedout according to the following reaction scheme.

Step D-14

A step of obtaining compound (d-27) by reacting compound (d-26) withcompound (d-17).

The reaction may be carried out under the same conditions described in,for example, M. Journet, D. Cai, R. D. Larsen and P. J. Reider,Tetrahedron Letters, 39, 1717 (1998).

Specifically, compound (d-27) may be obtained, for example, by addingcompound (d-17) and a base to a solution of compound (d-26) and stirringthe mixture for several hours to 1 day.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent. As examples of solvents there may bementioned methanol, ethanol, 2-propanol and tetrahydrofuran, but a2-propanol/tetrahydrofuran mixture is preferred. Examples of preferredbases include potassium carbonate and cesium carbonate. The base isusually used at 1-5 equivalents with respect to the starting material.The reaction temperature is not particularly restricted but willnormally be from freezing to the reflux temperature of the solvent.

Step D-15

A step of obtaining compound (d-28) by hydrolysis of compound (d-27)under acidic conditions.

The reaction may be carried out under the same conditions described in,for example, M. Journet, D. Cai, R. D. Larsen and P. J. Reider,Tetrahedron Letters, 39, 1717 (1998).

Specifically, compound (d-28) may be obtained, for example, by adding anacid such as hydrochloric acid to compound (d-27), stirring the mixturefor several hours to 1 day, and then treating it with a base such asaqueous sodium hydroxide.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and as examples there may bementioned methanol, ethanol, 2-propanol, tetrahydrofuran and acetone.Examples of preferred acids include hydrochloric acid, sulfuric acid andthe like. The acid is used in an amount of 1-20 equivalents with respectto the starting material. The reaction temperature is not particularlyrestricted but will normally be from room temperature to the refluxtemperature of the solvent.

Step D-14 and Step D-15 may be carried out in the same reactor withoutisolation of compound (d-27).

Step D-16

A step of obtaining compound (d-30) by reacting compound (d-28) andcompound (d-29).

The reaction may be carried out under the same conditions commonlyemployed for obtaining a pyridinium salt from a pyridine compound (forexample, the conditions described in C. K. Chu, V. S. Bhadti, K. J.Doshi, J. T. Etse, J. M. Gallo, F. D. Boudinot and R. F. Schinazi,Journal of Medicinal Chemistry, 33, 2188 (1990)).

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and as examples there may bementioned benzene, toluene, xylene, acetonitrile, methanol, ethanol and2-propanol. The reaction temperature is not particularly restricted butwill normally be from room temperature to the reflux temperature of thesolvent.

Step D-17

A step of obtaining compound (d-31) by reduction of compound (d-30). Thereaction may be carried out under the same conditions commonly employedfor reduction of a pyridinium salt to obtain a tetrahydropyridinecompound (for example, the conditions described in J. W. Beach, Journalof Heterocyclic Chemistry, 34, 1861 (1997)).

Sodium borohydride, potassium borohydride or the like is preferred asthe reducing agent for the reaction. There are no particularrestrictions on the solvent used for the reaction so long as it does notinhibit the reaction and dissolves the starting substances to someextent, and as examples there may be mentioned methanol, ethanol and2-propanol. The reaction temperature is not particularly restricted butwill normally be from freezing to the reflux temperature of the solvent.

Step D-18

A step of obtaining compound (d-32) by oxidation of compound (d-31). Thereaction may be carried out under the same conditions commonly employedfor oxidation of a secondary alcohol compound to a ketone compound, andspecifically it may be carried out under the same conditions as in StepD-2 above.

Step D-19

A step of obtaining compound (d-33) by reduction of compound (d-32).

The reaction may be carried out under the same conditions commonlyemployed for catalytic reduction from an unsaturated ketone compound toa saturated ketone compound under a hydrogen atmosphere (for example,the conditions described in R. L. Augustine, Journal of OrganicChemistry, 23, 1853 (1958)).

Palladium-carbon, palladium hydroxide-carbon, platinum oxide or the likeis preferred as the catalyst for the reaction. There are no particularrestrictions on the solvent used for the reaction so long as it does notinhibit the reaction and dissolves the starting substances to someextent, and as examples there may be mentioned methanol, ethanol and2-propanol. The reaction temperature is not particularly restricted butwill normally be from freezing to 100° C. The hydrogen pressure willusually be from ordinary pressure to 3 atmospheres.

(wherein (d-36) has the same definition as Z¹ above).Step D-20

A step of obtaining compound (d-35) by removing R^(x1) in compound(d-34).

When R^(x1) is used as an amine-protecting group, the removal of R^(x1)may be accomplished under the same conditions commonly employed for theparticular deprotecting reaction (for example, the conditions describedin T. W. Green and P. G. M. Wuts, “Protective Groups in OrganicChemistry, Second Edition”, John Wiley & Sons (1991), p. 309-405, J. H.Cooley and E. J. Evain, Synthesis, 1 (1989)).

For example, when R^(x1) is a tert-butoxycarbonyl group, compound (d-34)may be reacted with hydrogen chloride, hydrochloric acid, sulfuric acid,trifluoroacetic acid, p-toluenesulfonic acid or the like in an organicsolvent or in a mixture of water and an organic solvent.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction, butdichloromethane, methanol, ethanol, propanol, ethyl acetate,tetrahydrofuran, 1,4-dioxane and the like are preferred.

When R^(x1) is a benzyloxycarbonyl or benzyl group, the reaction may becarried out by catalytic reduction in an organic solvent under ahydrogen atmosphere, using palladium-carbon as the catalyst.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction, but methanol,ethanol, propanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane and thelike are preferred.

When R^(x1) is a benzyl group, the reaction may be carried out, forexample, with 1-chloroethyl chloroformate and methanol in that order, ina halogenated solvent such as 1,2-dichloroethane. The reactiontemperature is not particularly restricted but will normally be from−78° C. to the reflux temperature of the solvent, and preferably fromfreezing to the reflux temperature of the solvent.

[Production Scheme E]

Step E-1

A step of obtaining compound (e-3) by nucleophilic substitution withcompound (e-1) and compound (e-2).

The reaction may be carried out under the same conditions described in,for example, C. Z. Ding and A. V. Miller, Tetrahedron Letters, 37,4447-9450 (1996).

There are no particular restrictions on compound (e-2), and as preferredcompounds there may be mentioned sodium alkoxides such as sodiummethoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxideand sodium 4-methoxybenzyloxide, potassium alkoxides such as potassiummethoxide, potassium ethoxide, potassium isopropoxide, potassiumtert-butoxide and potassium 4-methoxybenzyloxide, and sodiumthioalkoxides such as sodium thiomethoxide, sodium thioethoxide, sodiumthioisopropoxide and sodium tert-butylthiolate.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and methanol, ethanol, propanol,tert-butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide andthe like may be mentioned as particularly preferred. The reactiontemperature is not particularly restricted but will normally be from−78° C. to the reflux temperature of the solvent, and preferably fromfreezing to the reflux temperature of the solvent.

Step E-2

A step of obtaining compound (e-4) by acylation of compound (e-3). Itmay be produced by reacting compound (e-3) with an organometallicreagent to form an anion, which is then reacted with a carboxylic acidderivative.

The reaction may be carried out under the same conditions described in,for example, R. J. Mattson and C. P. Sloan, Journal of OrganicChemistry, 55, 3410 (1990), A. Turck, D. Trohay, L. Mojovic, N. Ple andG. Queguiner, Journal of Organometallic Chemistry, 412, 301 (1991).

There are no particular restrictions on the organometallic reagent usedfor this reaction, and as preferred compounds there may be mentionedlithium reagents such as n-butyllithium, sec-butyllithium,tert-butyllithium and phenyllithium, lithium amide such as lithiumdiethylamide, lithium diisopropylamide, and lithium2,2,6,6-tetramethylpiperidide, or magnesium amide such asmethylmagnesium diisopropylamide, n-butylmagnesium diisopropylamide andn-butylmagnesium bis(diisopropylamide).

There are also no particular restrictions on the carboxylic acidderivative, and as preferred compounds there may be mentioned formicacid derivatives such as N,N-dimethylformamide, N-formylpiperidine,N-formylmorpholine, N-methyl-N-phenylformamide, methyl formate and ethylformate, or acetic acid derivatives such as acetylimidazolide andN-methoxy-N-methylacetamide.

Conducting the reaction in the copresence of a base may providefavorable results such as increased yield. The base used is notparticularly restricted and bases such asN,N,N′,N′-tetramethylethylenediamine may be mentioned as preferable. Thereaction temperature is not particularly restricted but will normally befrom −78° C. to the reflux temperature of the solvent, and preferablyfrom −78° C. to the room temperature. There are no particularrestrictions on the solvent used for the reaction so long as it does notinhibit the reaction, and there may be mentioned diethyl ether andtetrahydrofuran.

Step E-3

A step of producing compound (e-9) by reacting compound (e-7) and anorganometallic compound (e-8) in the presence of an organometalliccatalyst.

The reaction may be carried out under the same conditions commonlyemployed for coupling reaction between a halogenated heteroaryl compoundor the like and an organometallic compound in the presence of anorganometallic catalyst.

For example, a reaction using an organozinc reagent as theorganometallic compound is described in N. Sato and T. Matsuura, Journalof the Chemical Society: Perkin Transaction I, 2345 (1996), and areaction using an organoboron compound as the organometallic compound isdescribed in N. Miyaura, T. Yanagi, and A. Suzuki, SyntheticCommunications, 11, 513 (1981)

There are no particular restrictions on the organometallic catalyst usedfor the reaction, and as preferred compounds there may be mentionedtetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,palladium(II) acetate and [1,3-bis(diphenylphosphino)propane]nickel(II).The organometallic catalyst is used at about 0.001-0.1 equivalent withrespect to the starting material.

There are also no particular restrictions on the organometalliccompound, and there may be mentioned as preferable organozinc reagentssuch as dimethylzinc and diethylzinc, or organoboric acid compounds suchas methylboric acid. The organometallic compound is used at about 1-5equivalents with respect to the starting material.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction, and as preferredsolvents there may be mentioned benzene, toluene, N,N-dimethylformamide,1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile andpropionitrile. The reaction temperature is not particularly restrictedbut will normally be from freezing to the reflux temperature of thesolvent, and preferably from room temperature to the reflux temperatureof the solvent.

Conducting the reaction in the copresence of a base may providefavorable results such as increased yield. The base used is notparticularly restricted and bases such as sodium carbonate, potassiumcarbonate, cesium carbonate, potassium phosphate and triethylamine maybe mentioned as preferable.

Step E-4

A step of obtaining compound (e-10) by reduction of compound (e-9). Thereaction may be carried out under the same conditions commonly employedfor reduction of an ester compound to an aldehyde compound (for example,the conditions described in E. Winterfeldt, Synthesis, 617 (1975)).

Preferred as reducing agents to be used for the reaction arediisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminiumhydride, bis(N-methylpiperazino)aluminium hydride, and the like.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction and dissolves thestarting substances to some extent, and tetrahydrofuran, toluene anddichloromethane may be mentioned as preferable.

The reaction temperature is not particularly restricted but willnormally be from −78° C. to room temperature, and preferably from −78°C. to freezing.

Step E-5

A step of obtaining compound (e-12) by acetalization of compound (e-11).The reaction may be conducted under the same conditions commonlyemployed for acetalization of an aldehyde compound (for example, theconditions described in T. W. Green and P. G. M. Wuts, “ProtectiveGroups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991),p. 175-223, E. C. Taylor and C. S. Chiang, Synthesis, 467 (1977)).

For example, it may be carried out by reaction with hydrogen chloride inmethanol solution, or by reaction with methylorthoformate-montmorillonite K-10 in dichloromethane.

Step E-6

A step of producing compound (e-13) by reacting compound (e-12) and anorganometallic compound (e-8) in the presence of an organometalliccatalyst. The reaction may be carried out under the same conditions asin Step E-3.

Step E-7

A step of obtaining compound (e-10) by hydrolysis of compound (e-13).

The reaction may be conducted under the same conditions commonlyemployed for hydrolysis of an acetal compound (for example, theconditions described in T. W. Green and P. G. M. Wuts, “ProtectiveGroups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991),p. 175-223).

The reaction may be conducted in the presence of an acid, and examplesof acids which may be used include hydrochloric acid, p-toluenesulfonicacid, trifluoroacetic acid, camphorsulfonic acid and the like. There areno particular restrictions on the solvent used for the reaction so longas it does not inhibit the reaction and dissolves the startingsubstances to some extent, and preferred for use are solvents such asmethanol, ethanol, acetone and tetrahydrofuran, or mixtures of waterwith methanol, ethanol, acetone, tetrahydrofuran or the like.

Step E-8

A step of obtaining compound (e-7a) from compound (e-14) and a fluorinecompound (e-15).

The reaction may be conducted under the same conditions described in,for example, Y. Yoshida and Y. Kimura, Chemistry Letters, 1355 (1988),H. Egawa, Y. Furuta, J. Sugiura, S. Uehara, S. Hamamoto and K. Yonezawa,WO 01/60834.

Specifically, compound (e-7a) may be obtained, for example, by addingthe fluorine compound (e-15) to a solution of compound (e-14) andheating the mixture for several minutes to several hours.

There are no particular restrictions on the fluorine compound to be usedfor the reaction, and there may be mentioned lithium fluoride, sodiumfluoride, potassium fluoride, cesium fluoride and the like. The fluorinecompound is used at 1-10 equivalents with respect to the startingmaterial.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction, and as preferredsolvents there may be mentioned benzene, toluene, N,N-dimethylformamide,1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile,propionitrile and dimethylsulfoxide.

The reaction temperature is not particularly restricted but willnormally be from freezing to the reflux temperature of the solvent, andpreferably from room temperature to the reflux temperature of thesolvent.

The reaction may, if desired, be conducted in the copresence of a crownether such as 18-crown-6 or a phosphonium salt such astetraphenylphosphonium bromide, to achieve favorable results such asincreased yield and shortening of the reaction time.

Step E-9

A step of obtaining compound (e-11a) from compound (e-16) and a fluorinecompound (e-15). The reaction may be carried out under the sameconditions as in Step E-8.

Step E-10

A step of obtaining compound (e-18) by reacting compound (e-17) and analkenyl organometallic compound in the presence of an organometalliccatalyst.

The reaction may be carried out under the same conditions commonlyemployed for coupling reaction between a halogenated heteroaryl compoundor the like and an alkenyl organometallic compound in the presence of anorganometallic catalyst.

For example, a reaction using an organotin reagent as the alkenylorganometallic compound is described in D. R. McKean, G. Parrinello, A.F. Renaldo and J. K. Stille, Journal of Organic Chemistry, 52, 422(1987), a reaction using an organoboric acid compound as the alkenylorganometallic compound is described in N. Miyaura, T. Yanagi and A.Suzuki, Synthetic Communications, 11, 513 (1981), and a reaction using aGrignard reagent as the alkenyl organometallic compound is described inT. V. Lee, A. J. Leigh and C. B. Chapleo, Synthesis, 208 (1989).

There are no particular restrictions on the organometallic catalyst tobe used for this reaction, and as preferred compounds there may bementioned tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,palladium(II) acetate and [1,3-bis(diphenylphosphino)propane]nickel(II).

The organometallic catalyst is used at about 0.001-0.1 equivalent withrespect to the starting material.

There are also no particular restrictions on the alkenyl organometalliccompound, and there may be mentioned as preferable Grignard's reagentssuch as vinylmagnesium bromide, organotin compounds such astributyl(vinyl)tin, and organoboric acid compounds such as vinylboricacid.

There are no particular restrictions on the solvent used for thereaction so long as it does not inhibit the reaction, and as preferredsolvents there may be mentioned benzene, toluene, N,N-dimethylformamide,1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile andpropionitrile.

The reaction temperature is not particularly restricted but willnormally be from −78° C. to the reflux temperature of the solvent, andpreferably from 50° C. to 150° C. Conducting the reaction in thecopresence of a base may provide favorable results such as increasedyield. Such bases are not particularly restricted, and sodium carbonate,potassium carbonate, cesium carbonate, potassium phosphate andtriethylamine may be mentioned as preferable.

Step F-1

Compound (a-1a) may be synthesized using compound (f-1) as the startingmaterial, according to the method of Production Scheme E above.

Step F-2

Compound (a-3) may be synthesized using compound (f-2) as the startingmaterial, according to the method of Production Scheme E above.

Representative production schemes for compounds represented by generalformula (I) according to the invention have been described above, butthe starting compounds and reagents used for production of the compoundsof the invention may also form salts or hydrates which will differdepending on the starting materials and solvent used, and these are notparticularly restricted so long as the reaction is not inhibited. Thesolvents used will also differ depending on the starting materials andreagents, and they are not particularly restricted so long as they donot inhibit the reaction and dissolve the starting materials to someextent. When compound (I) of the invention is a free compound, a commonmethod may be used to convert it to a salt which compound (I) can form.The different isomers (for example, geometric isomers, and opticalisomers based on asymmetric carbons, rotational isomers andstereoisomers) obtained for compound (I) according to the invention maybe purified and isolated using common separation means such asrecrystallization, diastereomeric salt methods, enzymatic separationmethods and chromatography (for example, thin-layer chromatography,column chromatography, gas chromatography, etc.).

The compounds represented by formula (I) and salts thereof or hydratesof the foregoing exhibit excellent sodium channel-inhibiting activityand high safety (in terms of effects on the cardiovascular system,inhibiting action on hepatic drug metabolizing enzymes, enzymeinduction, etc.), and are therefore useful as drugs.

The compounds of the invention and salts thereof or hydrates of theforegoing may therefore be used to obtain pharmaceutical compositions(formulation) as therapeutic or prophylactic agents or analgesics, fordiseases wherein sodium channel inhibition is effective as treatment andprevention, such as various types of neuralgia (for example, diabeticneuralgia, HIV neuralgia, postherpetic neuralgia, trigeminal neuralgia,stump pain, post spinal injury pain, thalamic pain, post-stroke pain,etc.), epilepsy, insomnia, premature ejaculation, and the like.

Furthermore, administration of compounds of the invention, salts thereofor hydrates of the foregoing at pharmacologically effective doses topatients suffering from diseases or neuralgia wherein sodium channelinhibition is effective as treatment and prevention, may serve astreatment or prevention of such diseases or neuralgia.

The compounds of the invention, salts thereof or hydrates of theforegoing may be formulated as tablets, powders, fine particles,granules, coated tablets, capsules, syrups, lozenges, inhalants,suppositories, injections, ointments, eye salves, eye drops, nasaldrops, ear drops, paps, lotions and the like, by any common methods. Theformulation may employ any commonly used excipients, binders,lubricants, coloring agents, corrective coatings, and if necessary,stabilizers, emulsifiers, absorbefacients, surfactants, pH adjustors,preservatives, antioxidants, or the like, in combination with variouscomponents that are ordinarily used as raw materials for pharmaceuticalformulations.

As such components there may be mentioned animal and vegetable oils suchas soybean oil, beef tallow and synthetic glycerides; hydrocarbons suchas liquid paraffin, squalane and solid paraffin; ester oils such asoctyldodecyl myristate and isopropyl myristate; higher alcohols such ascetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils;surfactants such as polyoxyethylene fatty acid esters, sorbitan fattyacid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene hydrogenated castor oil andpolyoxyethylene-polyoxypropylene block copolymer; water-soluble polymerssuch as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer,polyethylene glycol, polyvinylpyrrolidone and methylcellulose; loweralcohols such as ethanol and isopropanol; polyhydric alcohols such asglycerin, propylene glycol, dipropylene glycol and sorbitol; sugars suchas glucose and sucrose; inorganic powders such as silicic acidanhydride, magnesium aluminium silicate and aluminium silicate, purifiedwater, and the like.

Examples of excipients which may be used include lactose, corn starch,white soft sugar, glucose, mannitol, sorbit, crystalline cellulose andsilicon dioxide, examples of binders which may be used include polyvinylalcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic,tragacanth, gelatin, shellac, hydroxypropylmethylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone, polypropyleneglycol/polyoxyethylene block polymer and meglumine, examples ofdisintegrators which may be used include starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium bicarbonate, calciumcitrate, dextrin, pectin and carboxymethylcellulose calcium, examples oflubricants which may be used include magnesium stearate, talc,polyethylene glycol, silica and hydrogenated vegetable oils, examples ofcoloring agents which may be used include those approved for addition todrugs, and examples of corrective coatings which may be used includecocoa powder, menthol, aromatic powders, mentha oil, borneol andpowdered cinnamon.

An oral formulation may be prepared by combining a compound of theinvention or pharmacologically acceptable salt thereof with anexcipient, if necessary adding a binder, disintegrator, lubricant,coloring agent, corrective coating or the like, and forming a powder,fine particles, granules, tablets, coated tablets, capsules, etc. by acommon method.

The tablets or granules may also be sugar coated or provided withanother type of suitable coating if necessary.

For preparation of a liquid formulation such as a syrup or injection, acommon method may be used to formulate a compound of the invention or apharmacologically acceptable salt thereof with a pH adjustor,solubilizer, isotonizing agent or the like, as well as a solubilizingaid, stabilizer etc. if necessary.

There are no particular restrictions on the method of preparing anexternal agent, and any common method may be employed. That is, it maybe prepared using as base materials any of various raw materials whichare ordinarily used in drugs, quasi drugs, cosmetics and the like. Asexamples of specific base materials there may be mentioned raw materialssuch as animal and vegetable oils, mineral oils, ester oils, waxes,higher alcohols, fatty acids, silicone oils, surfactants, phospholipids,alcohols, polyhydric alcohols, water-soluble polymers, clay minerals,purified water and the like, and if necessary pH adjustors,antioxidants, chelating agents, antiseptics and fungicides, coloringagents, aromas and the like may also be added, although the basematerials for external agents according to the invention are not limitedto these. If necessary, there may also be included components such ascirculation promoters, microbicides, antiphlogistic agents, cellactivators, vitamins, amino acids, humectants, keratolytic agents andthe like. The amounts of the aforementioned base materials may be theconcentrations established for preparation of ordinary external agents.

There are no particular restrictions on the compound of the invention,the salt thereof or the hydrate thereof when administered, and eitheroral or parenteral administration may be carried out according toordinary methods. For example, it may be prepared and administered inthe form of a tablet, powder, a granule, a capsule, syrup, lozenge,inhalant, suppository, injection, ointment, eye salve, eye drop, nasaldrop, ear drop, pap, lotion or the like. The dosage of a drug accordingto the invention may be appropriately selected depending on the age,gender, body weight and severity of symptoms of the patient, as well asthe specific type of condition, form of administration, type of salt,etc.

Although the dosage of a drug according to the invention will differdepending on the patient's type of disease, severity of symptoms, age,gender and drug sensitivity, it will generally be about 0.03-1000 mg andpreferably 0.1-500 mg per day for adults in the case of oraladministration or about 1-3000 μg/kg and preferably about 3-1000 μg/kgin the case of injection, and any such dosages may be administered onceor divided over several times a day.

The following are examples of formulations to be used for treatment orprevention in humans, which contain compounds selected from among thoseof Examples 140, 142, 143, 147, 157, 179, 184, 193, 233, 343, 344, 347,350, 365, 373, 376, 394 and 415, salts thereof or hydrates of theforegoing (Compound X).

Tablet 1 Content per tablet Compound X 100 mg Titanium oxide 11.2 mgTalc 4.0 mg Mannitol 106.7 mg Microcrystalline cellulose 60.0 mgLow-substituted hydroxypropylcellulose 20.0 mg Methacrylic acidcopolymer (type A) 80.0 mg Magnesium stearate 6.0 mg Hydroxypropylmethylcellulose 8.4 mg Coloring agent 5.6 mg Purified water quantum sufficit

Tablet 2 Content per tablet Compound X 25.0 mg Titanium oxide 2.8 mgTalc 4.0 mg Mannitol 199.2 mg Microcrystalline cellulose 60.0 mgLow-substituted hydroxypropylcellulose 20.0 mg Methacrylic acidcopolymer (type A) 80.0 mg Magnesium stearate 6.0 mg Hydroxypropylmethylcellulose 8.4 mg Coloring agent 5.6 mg Purified water quantum sufficit

Tablet 3 Content per tablet Compound X 2.5 mg Titanium oxide 0.28 mgTalc 1.0 mg Mannitol 54.42 mg Microcrystalline cellulose 15.0 mgLow-substituted hydroxypropylcellulose 5.0 mg Methacrylic acid copolymer(type A) 20.0 mg Magnesium stearate 1.5 mg Hydroxypropylmethyl cellulose3.6 mg Coloring agent 2.4 mg Purified water quantum sufficit

These formulations may be obtained by methods commonly used in the fieldof manufacturing pharmacy.

EXAMPLES

The following production examples, examples and test examples serve onlyfor the purpose of illustration and are not intended to be restrictiveon the compounds of the invention in any way. It will be apparent tothose skilled in the art that various modifications may be added beyondthese examples and within the scope of the claims of the invention inthe present specification in order to maximize the effect of theinvention, and such modifications are also encompassed within theclaims.

Production Example 1 3-tert-Butoxypyrazine-2-carboxaldehyde

After dissolving 2.50 ml of 2,2,6,6-tetramethylpiperidine in 40 ml oftetrahydrofuran, the solution was cooled to −50° C. Next, 5.25 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise theretounder a nitrogen atmosphere. The mixture was stirred for 25 minutes,cooled on ice, and stirred for an additional 35 minutes. It was thencooled to −78° C., and a solution of 1.89 g of 2-tert-butoxypyrazine[CAS No. 70090-30-1] in tetrahydrofuran (5 ml) was added dropwise. Afterstirring the mixture for 15 minutes, 1.25 ml of N, N-dimethylformamidewas added dropwise. After 10 minutes, water was added to the reactionsolution and extraction was performed with ethyl acetate. The organiclayer was washed with water and saturated brine in that order and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (1.00 g, 45% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68 (9H, s), 8.28 (1H, d, J=2.4 Hz),8.30 (1H, d, J=2.4 Hz), 10.33 (1H, s).

Production Example 2 3-(tert-Butylthio)pyrazine-2-carboxaldehyde

The title compound (1.49 g, 40% yield) was obtained in the same manneras Production Example 1 from 3.22 g of 2-(tert-butylthio)pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.65 (9H, s), 8.40 (1H, d, J=2.4 Hz),8.53 (1H, d, J=2.4 Hz), 10.14 (1H, s).

Production Example 3 3-tert-Butoxyquinoxaline-2-carboxaldehyde

The title compound (0.84 g, 18% yield) was obtained in the same manneras Production Example 1 from 4.00 g of 2-tert-butoxyquinoxaline.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78 (9H, s), 7.61 (1H, ddd, J=8.4, 7.2,1.6 Hz), 7.77 (1H, ddd, J=8.4, 7.2, 1.6 Hz), 7.84 (1H, ddd, J=8.4, 1.6,0.8 Hz), 8.15 (1H, ddd, J=8.4, 1.6, 0.8 Hz), 10.48 (1H, s).

Production Example 4 2-tert-Butoxy-6-chloropyrazine

After dissolving 3.00 g of 2,6-dichloropyrazine in 40 ml oftetrahydrofuran, 2.26 g of potassium tert-butoxide was added and themixture was stirred for 5.5 hours at room temperature. The reactionsolution was distilled off under reduced pressure, ethyl acetate wasadded to the residue and filtration was performed with NH silica gel andsilica gel. The solvent was distilled off under reduced pressure toobtain the title compound (3.38 g, 90% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 7.99 (1H, s), 8.06 (1H,s).

Production Example 5 2-(tert-Butylthio)pyrazine

After dissolving 2.305 g of 2-chloropyrazine in 60 ml oftetrahydrofuran, 2.76 g of sodium tert-butylthiolate was added whilestirring and the mixture was heated to reflux for 3 hours. Water wasadded to the reaction solution and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine inthat order and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. Ethyl acetate wasadded to the residue and filtration was performed with NH silica gel andsilica gel. The solvent was distilled off under reduced pressure toobtain the title compound (3.217 g, 95% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54 (9H, s), 8.28 (1H, d, J=2.8 Hz),8.44 (1H, dd, J=2.8, 1.6 Hz), 8.50 (1H, d, J=1.6 Hz).

Production Example 6 2-tert-Butoxyquinoxaline

The title compound (5.99 g, 98% yield) was obtained in the same manneras Production Example 4 from 5.00 g of 2-chloroquinoxaline.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.71 (9H, s), 7.53 (1H, ddd, J=8.4, 7.2,1.6 Hz), 7.64 (1H, ddd, J=8.4, 7.2, 1.6 Hz), 7.80 (1H, ddd, J=8.4, 1.6,0.4 Hz), 7.97 (1H, ddd, J=8.4, 1.6, 0.4 Hz), 8.34 (1H, s).

Production Example 7 2-tert-Butoxy-4-chloropyrimidine and4-tert-butoxy-2-chloropyrimidine

After dissolving 2.00 g of 2,4-dichloropyrimidine in 30 ml oftert-butanol, 1.58 g of potassium tert-butoxide was added while stirringand the mixture was stirred overnight at room temperature. The reactionmixture was poured onto ice and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine inthat order and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate), to obtain 2-tert-butoxy-4-chloropyrimidine (0.40 g, 16% yield)and 4-tert-butoxy-2-chloropyrimidine (1.28 g, 50% yield).

2-tert-Butoxy-4-chloropyrimidine

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.63 (9H, s), 6.91 (1H, d, J=1.6 Hz),8.34 (1H, d, J=1.6 Hz).

4-tert-Butoxy-2-chloropyrimidine

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.62 (9H, s), 6.53 (1H, d, J=1.6 Hz),8.22 (1H, d, J=1.6 Hz).

Production Example 8 2-tert-Butoxy-6-vinylpyrazine

After dissolving 5.25 g of 2-tert-butoxy-6-chloropyrazine in 80 ml ofN,N-dimethylformamide, 9.66 g of tributyl(vinyl)tin and 0.97 g ofdichlorobis(triphenylphosphine) palladium (II) were added and themixture was stirred for 8 hours and 30 minutes at 80° C. under anitrogen atmosphere. Saturated brine and ethyl acetate were added to thereaction solution, and the insoluble portion was filtered off. The ethylacetate layer was washed with water and saturated brine in that orderand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate) to obtainthe title compound (4.24 g, 85% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.63 (9H, s), 5.50 (1H, dd, J=10.8, 1.6Hz), 6.31 (1H, dd, J=17.2, 1.6 Hz), 6.70 (1H, dd, J=17.2, 10.8 Hz), 7.95(1H, s), 7.96 (1H, s).

Production Example 9 4-tert-Butoxy-2-vinylpyrimidine

The title compound (2.26 g, 79% yield) was obtained in the same manneras Production Example 8 from 3.00 g of 4-tert-butoxy-2-chloropyrimidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.64 (9H, s), 5.66 (1H, dd, J=10.4, 1.6Hz), 6.46 (1H, d, J=6.0 Hz), 6.51 (1H, dd, J=15.2, 1.6 Hz), 6.77 (1H,dd, J=15.2, 10.4 Hz), 8.32 (1H, d, J=6.0 Hz).

Production Example 10 2-tert-Butoxy-4-vinylpyrimidine

The title compound (2.04 g, 81% yield) was obtained in the same manneras Production Example 8 from 2.64 g of 2-tert-butoxy-4-chloropyrimidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.65 (9H, s), 5.64 (1H, dd, J=10.4, 1.6Hz), 6.44 (1H, dd, J=17.2, 1.6 Hz), 6.65 (1H, dd, J=17.2, 10.4 Hz), 8.12(1H, d, J=5.2 Hz), 8.42 (1H, d, J=5.2 Hz).

Production Example 111-(1-Benzylpiperidin-4-yl)-2-(2-fluorophenyl)ethanol

After suspending 1.84 g of magnesium in 20 ml of diethyl ether, acatalytic amount of iodine was added, a portion of a diethyl ethersolution (70 ml) containing 9.97 g of 2-fluorobenzyl chloride was addeddropwise while stirring, and the mixture was heated to initiate thereaction. The remaining solution was then added dropwise at a rate tomaintain reflux. After 10 minutes, the mixture was cooled on ice, adiethyl ether solution (70 ml) containing 15.4 g of1-benzyl-4-piperidinecarboxaldehyde [CAS No. 22065-85-6] was addeddropwise, and stirring was continued for 20 minutes. Saturated aqueousammonium chloride solution was added to the reaction solution andextraction was performed with ethyl acetate. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (13.4 g, 62% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.75 (4H, m), 1.82-1.90 (1H, m),1.90-2.00 (2H, m), 2.57-2.65 (2H, m), 2.90-3.02 (3H, m), 3.50 (2H, s),3.62-3.68 (1H, m), 7.03 (1H, ddd, J=9.6, 8.0, 1.2 Hz), 7.08 (1H, td,J=8.0, 1.6 Hz), 7.18-7.34 (7H, m).

Production Example 122-(1-Benzylpiperidin-4-yl)-1-(2-fluorophenyl)ethanol

After dissolving 1.64 ml of 1-bromo-2-fluorobenzene in 30 ml oftetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise whilestirring, and after 1 hour, a solution of 2.50 g of1-benzyl-4-piperidineacetaldehyde [CAS No. 120014-32-6] intetrahydrofuran (10 ml) was added and stirring was continued for 1 hour.After adding water to the reaction solution, the temperature was raisedto room temperature and extraction was performed with ethyl acetate. Theorganic layer was washed with water and saturated brine in that orderand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (2.15 g, 60% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.25-1.38 (2H, m), 1.41-1.52 (1H, m),1.56-1.81 (4H, m), 1.90-1.98 (2H, m), 2.82-2.90 (2H, m), 3.47 (2H, s),5.10 (1H, dd, J=8.4, 4.8 Hz), 7.01 (1H, ddd, J=10.4, 8.0, 1.2 Hz), 7.14(1H, dt, J=7.2, 1.2 Hz), 7.20-7.32 (6H, m), 7.45 (1H, dt, J=7.6, 1.6Hz).

Production Example 132-(1-Benzylpiperidin-4-yl)-1-(2-methoxyphenyl)ethanol

After dissolving 2.04 g of 2-bromoanisole in 22 ml of tetrahydrofuran,3.6 ml of n-butyllithium (2.66 M, n-hexane solution) was added dropwisewhile stirring at below −60° C., and after 30 minutes, a solution of1.58 g of 1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (5 ml)was added and stirring was continued for 30 minutes. Saturated aqueousammonium chloride solution was added, the temperature was raised to roomtemperature, and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by NH silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (1.63 g, 69% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.22-1.38 (2H, m), 1.45-1.65 (2H, m),1.67-1.75 (1H, m), 1.75-1.84 (2H, m), 1.91-1.99 (2H, m), 2.83-2.91 (2H,m), 3.47 (2H, s), 3.84 (3H, s), 4.94-5.01 (1H, m), 6.87 (1H, dd, J=8.4,1.2 Hz), 6.95 (1H, td, J=7.6, 1.2 Hz), 7.21-7.33 (7H, m).

Production Example 142-(1-Benzylpiperidin-4-yl)-1-(3-chloro-2-thienyl)ethanol

After dissolving 1.3 ml of diisopropylamine in 20 ml of tetrahydrofuran,3.5 ml of n-butyllithium (2.66 M, n-hexane solution) was added dropwisewhile stirring at below −30° C. After stirring for 30 minutes whilecooling on ice, 0.86 ml of 3-chlorothiophene was added dropwise. Themixture was stirred for another 30 minutes, and then a solution of 1.68g of 1-benzyl-4-piperidineacetaldehyde in tetrahydrofuran (5 ml) wasadded and stirring was continued for 1 hour. Saturated aqueous ammoniumchloride solution was added to the reaction solution and extraction wasperformed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (1.53 g, 59% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.26-1.54 (3H, m), 1.56-1.88 (4H, m),1.90-1.98 (2H, m), 2.83-2.91 (2H, m), 3.49 (2H, s), 5.19 (1H, dd, J=8.4,5.6 Hz), 6.86 (1H, d, J=5.2 Hz), 7.21-7.34 (6H, m).

Production Example 151-(1-Benzylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone

After dissolving 7.5 ml of oxalyl chloride in 130 ml of dichloromethane,the solution was cooled to −78° C. and a solution of 6.1 ml ofdimethylsulfoxide in dichloromethane (20 ml) was added dropwise whilestirring. After stirring for 20 minutes, a solution of 13.4 g of1-(1-benzylpiperidin-4-yl)-2-(2-fluorophenyl)ethanol in dichloromethane(40 ml) was added dropwise. After stirring for 30 minutes, 24 ml oftriethylamine was added and the temperature was raised to roomtemperature. Water was added to the reaction solution, the organic layerwas washed with water and saturated brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by NH silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (9.64 g, 73% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68-1.80 (2H, m), 1.81-1.88 (2H, m),1.97-2.06 (2H, m), 2.40-2.49 (1H, m), 2.88-2.95 (2H, m), 3.50 (2H, s),3.77 (2H, d, J=1.2 Hz), 7.04 (1H, ddd, J=9.6, 7.8, 1.2 Hz), 7.09 (1H,td, J=7.8, 1.2 Hz), 7.16 (1H, td, J=7.8, 2.0 Hz), 7.21-7.34 (6H, m).

Production Example 161-(1-Benzylpiperidin-4-yl)-2-(2-methoxyphenyl)ethanone

After dissolving 1.34 g of o-anisaldehyde in 10 ml of methanol, 1.83 gof p-toluenesulfonyl hydrazide was added, the mixture was stirred for 2hours at room temperature and then 725 mg of potassium methoxide and asolution of 1.00 g of 1-benzylpiperidine-4-carboxaldehyde in methanol (3ml) was added, and the mixture was shielded from light and stirredovernight at 55° C. Water was added to the reaction solution, andextraction was performed with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent:toluene/ethyl acetate) to obtain the title compound (249 mg, 16% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.67-1.86 (4H, m), 1.94-2.03 (2H, m),2.39-2.48 (1H, m), 2.87-2.94 (2H, m), 3.49 (2H, s), 3.71 (2H, s), 3.77(3H, s), 6.85 (1H, d, J=7.4 Hz), 6.91 (1H, td, J=7.4, 1.2 Hz), 7.09 (1H,dd, J=7.4, 2.0 Hz), 7.16-7.33 (6H, m).

Production Example 171-(1-Benzylpiperidin-4-yl)-2-(3-fluorophenyl)ethanone

The title compound (283 mg, 8% yield) was obtained in the same manner asProduction Example 16 from 3.0 g of 3-fluorobenzaldehyde and 2.45 g of1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.65-1.84 (4H, m), 1.94-2.03 (2H, m),2.37-2.46 (1H, m), 2.86-2.94 (2H, m), 3.49 (2H, s), 3.73 (2H, s),6.87-6.98 (3H, m), 7.22-7.35 (6H, m).

Production Example 181-(1-Benzylpiperidin-4-yl)-2-(3-methylphenyl)ethanone

The title compound (241 mg, 16% yield) was obtained in the same manneras Production Example 16 from 1.18 g of m-tolualdehyde and 1.00 g of1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.63-1.82 (4H, m), 1.92-2.02 (2H, m),2.33 (3H, s), 2.37-2.46 (1H, m), 2.85-2.93 (2H, m), 3.48 (2H, s), 3.69(2H, s), 6.94-7.00 (2H, m), 7.04-7.08 (1H, m), 7.17-7.34 (6H, m).

Production Example 191-(1-Benzylpiperidin-4-yl)-2-(2-chlorophenyl)ethanone

The title compound (252 mg, 20% yield) was obtained in the same manneras Production Example 16 from 1.0 g of 2-chlorobenzaldehyde and 789 mgof 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.71-1.82 (2H, m), 1.84-1.91 (2H, m),1.98-2.06 (2H, m), 2.42-2.52 (1H, m), 2.89-2.96 (2H, m), 3.50 (2H, s),3.89 (2H, s), 7.08-7.20 (9H, m).

Production Example 201-(1-Benzylpiperidin-4-yl)-2-(2,5-difluorophenyl)ethanone

The title compound (215 mg, 13% yield) was obtained in the same manneras Production Example 16 from 1.40 g of 2,5-difluorobenzaldehyde and1.00 g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68-1.80 (2H, m), 1.82-1.90 (2H, m),1.98-2.07 (2H, m), 2.40-2.49 (1H, m), 2.89-2.96 (2H, m), 3.51 (2H, s),3.75 (2H, d, J=1.2 Hz), 6.85-7.03 (3H, m), 7.22-7.34 (5H, m).

Production Example 211-(1-Benzylpiperidin-4-yl)-2-(2,6-difluorophenyl)ethanone

The title compound (65 mg, 4% yield) was obtained in the same manner asProduction Example 16 from 1.40 g of 2,6-difluorobenzaldehyde and 1.00 gof 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.84 (2H, m), 1.85-1.94 (2H, m),1.99-2.08 (2H, m), 2.42-2.53 (1H, m), 2.89-2.97 (2H, m), 3.51 (2H, s),3.81 (2H, s), 6.84-6.92 (2H, m), 7.16-7.34 (6H, m).

Production Example 221-(1-Benzylpiperidin-4-yl)-2-(2-methylphenyl)ethanone

The title compound (998 mg, 26% yield) was obtained in the same manneras Production Example 16 from 3.0 g of o-tolualdehyde and 2.54 g of1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68-1.83 (4H, m), 1.94-2.02 (2H, m),2.20 (3H, s), 2.38-2.48 (1H, m), 2.87-2.94 (2H, m), 3.49 (2H, s), 3.75(2H, s), 7.04-7.10 (1H, m), 7.12-7.18 (3H, m), 7.22-7.34 (5H, m).

Production Example 232-(1-Benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanone

After dissolving 1.75 ml of 1-bromo-2-chlorobenzene in 30 ml oftetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise theretowhile stirring and after 1 hour, a solution of 2.50 g of1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (10 ml) was addedand stirring was continued for 1 hour. After adding water to thereaction solution, the temperature was raised to room temperature andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure to obtain2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanol.

After dissolving 1.30 ml of oxalyl chloride in 30 ml of dichloromethane,the solution was cooled to −78° C., and a solution of 1.22 ml ofdimethylsulfoxide in dichloromethane (5 ml) was added dropwise whilestirring. The mixture was stirred for 3 minutes, and then a solution of2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanol in dichloromethane(10 ml) was added dropwise. After stirring for 30 minutes, 8.01 ml oftriethylamine was added, the temperature was raised to room temperatureand stirring was continued for 3 hours. Water was added to the reactionsolution, and extraction was performed with ethyl acetate. The organiclayer was washed with water and saturated brine in that order and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by NH silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (1.78 g, 47% yield, 2 steps).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.29-1.41 (2H, m), 1.69-1.76 (2H, m),1.92-2.04 (3H, m), 2.83-2.89 (4H, m), 3.48 (2H, s), 7.21-7.42 (9H, m).

Production Example 242-(1-Benzylpiperidin-4-yl)-1-(3-chloro-2-thienyl)ethanone

The title compound (682 mg, 90% yield) was obtained in the same manneras Production Example 15 from 758 mg of2-(1-benzylpiperidin-4-yl)-1-(3-chloro-2-thienyl)ethanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.32-1.44 (2H, m), 1.71-1.78 (2H, m),1.94-2.08 (3H, m), 2.84-2.90 (2H, m), 2.93 (2H, d, J=6.8 Hz), 3.49 (2H,s), 7.01 (1H, d, J=5.2 Hz), 7.21-7.33 (5H, m), 7.52 (1H, d, J=5.2 Hz).

Production Example 252-(1-Benzylpiperidin-4-yl)-1-(2-fluorophenyl)ethanone

The title compound (2.31 g, 84% yield) was obtained in the same manneras Production Example 15 from 2.77 g of2-(1-benzylpiperidin-4-yl)-1-(2-fluorophenyl)ethanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.29-1.41 (2H, m), 1.68-1.76 (2H, m),1.92-2.04 (3H, m), 2.83-2.92 (4H, m), 3.49 (2H, s), 7.12 (1H, ddd,J=9.6, 8.0, 1.2 Hz), 7.19-7.32 (6H, m), 7.47-7.53 (1H, m), 7.81 (1H, dt,J=7.2, 2.0 Hz).

Production Example 261-[1-(tert-Butoxycarbonyl)piperidin-3-yl]-2-(2-fluorophenyl)ethanone

After suspending 334 mg of magnesium in 3 ml of diethyl ether, acatalytic amount of iodine was added, a portion of 1.89 g of2-fluorobenzyl chloride was added dropwise while stirring, and themixture was heated to initiate the reaction. After adding 10 ml ofdiethyl ether, the remaining 2-fluorobenzyl chloride was added dropwiseto maintain reflux. After stirring the mixture for 15 minutes,approximately 6 ml of the obtained reaction solution was added dropwiseto a solution of 1.78 g ofN-methoxy-N-methyl-1-(tert-butoxycarbonyl)-3-piperidinecarboxamide [CASNo. 189442-78-2] in diethyl ether (20 ml) while cooling on ice, andstirring was continued for 30 minutes. Saturated aqueous ammoniumchloride solution was added to the reaction solution and extraction wasperformed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (564 mg, 27% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.67 (2H, m), 1.46 (9H, s),1.68-1.80 (1H, m), 1.96-2.07 (1H, m), 2.60-2.87 (2H, m), 2.99 (1H, dd,J=13.4, 10.2 Hz), 3.75-4.25 (4H, m), 7.02-7.19 (3H, m), 7.22-7.32 (1H,m).

Production Example 271-(1-Benzylpiperidin-4-yl)-2-(2-fluoro-3-thienyl)ethanone

After dissolving 292 mg of1-benzyl-4-[2-(2-fluoro-3-thienyl)acetyl]-1,2,3,6-tetrahydropyridine in10 ml of ethanol, 0.1 g of 20% palladium hydroxide-carbon (hydrous) wasadded and the mixture was stirred for 1 hour at room temperature under ahydrogen atmosphere (1 atm). The reaction mixture was filtered and thefiltrate was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (239 mg, 81% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.65-1.86 (4H, m), 1.96-2.05 (2H, m),2.37-2.46 (1H, m), 2.87-2.94 (2H, m), 3.49 (2H, s), 3.64 (2H, d, J=0.8Hz), 6.60-6.62 (2H, m), 7.22-7.34 (5H, m).

Production Example 28 1-(2-Methoxyphenyl)-2-(piperidin-4-yl)ethanone

After dissolving 1.63 g of2-(1-benzylpiperidin-4-yl)-1-(2-methoxyphenyl)ethanol in 5 ml ofdimethylsulfoxide, 4.2 ml of triethylamine was added, a solution of 2.39g of sulfur trioxide-pyridine complex in dimethylsulfoxide (15 ml) wasadded dropwise and the mixture was stirred for 30 minutes at roomtemperature. Water was added to the reaction mixture, and extraction wasperformed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain 1.38 g of1-(1-benzylpiperidin-4-yl)-2-(2-methoxyphenyl)ethanone. After dissolvingthis in 12 ml of 1,2-dichloroethane, 0.55 ml of 1-chloroethylchloroformate was added while stirring on ice, and the mixture washeated to reflux for 1 hour. The solvent was distilled off under reducedpressure, 10 ml of methanol was added to the residue and heating toreflux was continued for 30 minutes. The solvent was distilled off underreduced pressure. A 1N sodium hydroxide solution was added to theresidue and extraction was performed with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressureto obtain the title compound (750 mg, 64% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.15-1.27 (2H, m), 1.68-1.80 (2H, m),2.02-2.12 (1H, m), 2.59-2.68 (2H, m), 2.89 (2H, d, J=6.8 Hz), 3.02-3.08(2H, m), 3.90 (3H, s), 6.96 (1H, d, J=8.6 Hz), 7.00 (1H, td, J=7.6, 1.2Hz), 7.45 (1H, ddd, J=8.6, 7.6, 1.8 Hz), 7.62 (1H, dd, J=7.6, 1.8 Hz).

Production Example 29 2-(2-Fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride

After dissolving 1.27 g of1-(1-benzylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone in 8 ml of1,2-dichloroethane, 0.53 ml of 1-chloroethyl chloroformate was addedwhile stirring on ice, and the mixture was heated to reflux for 1 hour.The solvent was distilled off under reduced pressure, 8 ml of methanolwas added to the residue, and heating to reflux was continued for 40minutes. The solvent was distilled off under reduced pressure, ethylacetate was added to the residue, and the precipitate was filtered outto obtain the title compound (970 mg, 92% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.63-1.76 (2H, m), 1.99-2.07 (2H, m),2.82-2.96 (3H, m), 3.23-3.31 (2H, m), 3.95 (2H, s), 7.12-7.19 (2H, m),7.23-7.35 (2H, m), 8.94 (2H, br s).

Production Example 30 2-(2-Methylphenyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (680 mg, 82% yield) was obtained in the same manneras Production Example 29 from 998 mg of1-(1-benzylpiperidin-4-yl)-2-(2-methylphenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.60-1.72 (2H, m), 1.97-2.05 (2H, m),2.11 (3H, s), 2.81-2.97 (3H, m), 3.24-3.31 (2H, m), 3.91 (2H, s),7.08-7.17 (4H, m).

Production Example 31 1-(2-Fluorophenyl)-2-(piperidin-4-yl)ethanonehydrochloride

The title compound (2.09 g, 68% yield) was obtained in the same manneras Production Example 29 from 3.71 g of2-(1-benzylpiperidin-4-yl)-1-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68-1.82 (2H, m), 1.96-2.04 (2H, m),2.24-2.38 (1H, m), 2.86-3.02 (4H, m), 3.46-3.54 (2H, m), 7.15 (1H, ddd,J=11.2, 8.4, 1.2 Hz), 7.24 (1H, dt, J=8.4, 1.2 Hz), 7.51-7.57 (1H, m),7.84 (1H, dt, J=7.6, 2.0 Hz), 9.39 (1H, br s), 9.67 (1H, br s).

Production Example 32 1-(2-Chlorophenyl)-2-(piperidin-4-yl)ethanonehydrochloride

The title compound (1.15 g, 78% yield) was obtained in the same manneras Production Example 29 from 1.78 g of2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.69-1.83 (2H, m), 1.96-2.04 (2H, m),2.30 (1H, m), 2.86-3.00 (4H, m), 3.46-3.54 (2H, m), 7.31-7.44 (4H, m),9.38 (1H, br s), 9.63 (1H, br s).

Production Example 33 1-(3-Chloro-2-thienyl)-2-(piperidin-4-yl)ethanonehydrochloride

The title compound (520 mg, 91% yield) was obtained in the same manneras Production Example 29 from 682 mg of2-(1-benzylpiperidin-4-yl)-1-(3-chloro-2-thienyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.70-1.84 (2H, m), 1.98-2.06 (2H, m),2.24-2.36 (1H, m), 2.88-2.98 (2H, m), 3.03 (2H, d, J=6.4 Hz), 3.46-3.54(2H, m), 7.04 (1H, d, J=5.2 Hz), 7.57 (1H, d, J=5.2 Hz).

Production Example 34 2-(2-Fluoro-3-thienyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (173 mg, 88% yield) was obtained in the same manneras Production Example 29 from 239 mg of1-(1-benzylpiperidin-4-yl)-2-(2-fluoro-3-thienyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.61-1.73 (2H, m), 1.96-2.04 (2H, m),2.79-2.96 (3H, m), 3.22-3.30 (2H, m), 3.82 (2H, s), 6.89 (1H, dd, J=6.0,4.0 Hz), 6.93 (1H, dd, J=6.0, 4.0 Hz), 8.74 (1H, br s), 9.03 (1H, br s).

Production Example 351-Benzyl-4-[2-(2-fluoro-3-thienyl)acetyl]-1,2,3,6-tetrahydropyridine

The title compound (292 mg, 77% yield) was obtained in the same manneras Production Example 15 from 384 mg of1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-fluoro-3-thienyl)ethanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.37-2.43 (2H, m), 2.60 (2H, t, J=5.6Hz), 3.19-3.23 (2H, m), 3.62 (2H, s), 3.85 (2H, s), 6.60 (1H, dd, J=6.0,4.0 Hz), 6.63 (1H, dd, J=6.0, 3.6 Hz), 6.88-6.92 (1H, m), 7.24-7.35 (5H,m).

Production Example 361-(tert-Butoxycarbonyl)-4-[(2-fluorophenyl)ethynyl]-4-hydroxypiperidine

After dissolving 12.6 g of carbon tetrabromide in 80 ml ofdichloromethane, the solution was cooled to 0° C. A 20 g portion oftriphenylphosphine was added thereto in small portions at a time, andthe mixture was stirred for 1 hour. A solution of 2.4 g of2-fluorobenzaldehyde in dichloromethane (70 ml) was added dropwise andstirring was continued at 0° C. for 4 hours. After stirring overnight atroom temperature, hexane was added and the mixture was filtered. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate). The obtained 3.7 g of 1,1-dibromo-2-(2-fluorophenyl)ethene wasdissolved in 30 ml of tetrahydrofuran, and the solution was cooled to−78° C. Next, 18 ml of n-butyllithium (1.6 M, n-hexane solution) wasadded dropwise. The mixture was stirred at −78° C. for 1 hour and thenat room temperature for 1 hour. The obtained reaction solution was addeddropwise to a solution of 2.6 g of tert-butyl4-oxo-1-piperidinecarboxylate in tetrahydrofuran (100 ml) which had beencooled to −78° C. After stirring the mixture for 4 hours while slowlyraising the temperature to room temperature, saturated aqueous ammoniumchloride solution was added and extraction was performed with ethylacetate. The organic layer was dried over magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (1.4 g, 23% yield, 2 steps).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47 (9H, s), 1.76-1.83 (2H, m),1.99-2.05 (2H, m), 3.27-3.35 (2H, m), 3.81-3.90 (2H, m), 7.05-7.12 (2H,m), 7.28-7.36 (1H, m), 7.39-7.44 (1H, m).

Production Example 371-(tert-Butoxycarbonyl)-4-hydroxy-4-[(2-methylphenyl)ethynyl]piperidine

The title compound (3.99 g, 79% yield) was obtained in the same manneras Example 36 from 2.29 g of 2-methylbenzaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47 (9H, s), 1.77-1.84 (2H, m),1.98-2.05 (2H, m), 2.42 (3H, s), 3.27-3.35 (2H, m), 3.81-3.95 (2H, m),7.11-7.16 (1H, m), 7.19-7.26 (2H, m), 7.38-7.41 (1H, m).

Production Example 381-(tert-Butoxycarbonyl)-4-cyano-4-(methanesulfonyloxymethyl)piperidine

After dissolving 537 mg of1-(tert-butoxycarbonyl)-4-cyano-4-(hydroxymethyl)piperidine in 100 ml oftetrahydrofuran, 0.4 ml of triethylamine was added and the solution wascooled to 0° C. 0.2 ml of methanesulfonyl chloride was added and themixture was stirred overnight at room temperature. The reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.After adding water to the residue, extraction was performed with ethylacetate. The organic layer was washed with water and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain the title compound (799 mg, 100% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.95-2.05 (2H, m),1.50-1.57 (2H, m), 3.00-3.10 (2H, m), 3.13 (3H, s), 4.13-4.30 (2H, m),4.19 (2H, s).

Production Example 391-(tert-Butoxycarbonyl)-4-fluoro-4-(methanesulfonyloxymethyl)piperidine

The title compound (150 mg, 100% yield) was obtained in the same manneras Example 38 from 103 mg of1-(tert-butoxycarbonyl)-4-fluoro-4-(hydroxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.48-1.94 (4H, m),3.09-3.18 (2H, m), 3.08 (3H, s), 3.95-4.05 (2H, m), 4.20 (2H, d, J=20.0Hz).

Production Example 407-(tert-Butoxycarbonyl)-2-methanesulfonyloxy-7-azaspiro[3.5]nonane

After dissolving 106 mg of7-(tert-butoxycarbonyl)-2-hydroxy-7-azaspiro[3.5]nonane in 10 ml oftetrahydrofuran, 0.04 ml of methanesulfonyl chloride and 0.07 ml oftriethylamine were added and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. After adding water to the residue,extraction was performed with ethyl acetate. The organic layer waswashed with water and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (148 mg, 100% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45 (9H, s), 1.52-1.63 (4H, m), 2.08(1H, dd, J=10.4, 7.2 Hz), 2.09 (1H, dd, J=10.4, 7.2 Hz), 2.41 (1H, dd,J=10.4, 7.2 Hz), 2.43 (1H, dd, J=10.4, 7.2 Hz), 2.99 (3H, s), 3.29-3.30(4H, m), 5.03 (1H, quintet, J=7.2 Hz).

Production Example 411-(tert-Butoxycarbonyl)-4-cyano-4-(2-methylphenoxymethyl)piperidine

After dissolving 230 mg of 2-methylphenol in 20 ml ofN,N-dimethylformamide, 43 mg of sodium hydride (70% suspension in oil)was added and the mixture was stirred at 80° C. for 30 minutes. Next,224 mg of1-(tert-butoxycarbonyl)-4-cyano-4-(methanesulfonyloxymethyl)piperidinewas added and the mixture was stirred at 100° C. for 8 hours. Aftercooling it to room temperature, water was added and extraction wasperformed with ethyl acetate. The organic layer was washed with a 1Nsodium hydroxide solution and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (273 mg, 100% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.48 (9H, s), 1.65 (2H, td, J=13.2, 4.4Hz), 2.07-2.12 (2H, m), 2.27 (3H, s), 3.01-3.19 (2H, m), 3.98 (2H, s),4.15-4.28 (2H, m), 6.74-6.77 (1H, m), 6.92 (1H, td, J=7.6, 1.2 Hz),7.09-7.19 (2H, m).

Production Example 421-(tert-Butoxycarbonyl)-4-cyano-4-(2-fluorophenoxymethyl)piperidine

The title compound (239 mg, 100% yield) was obtained in the same manneras Example 41 from 83 mg of 2-fluorophenol and 212 mg of1-(tert-butoxycarbonyl)-4-cyano-4-(methanesulfonyloxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.48 (9H, s), 1.67 (2H, td, J=13.4, 4.4Hz), 2.08 (2H, d, J=12.0 Hz), 3.00-3.20 (2H, m), 4.05 (2H, s), 4.10-4.30(2H, m), 6.96-7.03 (2H, m), 7.04-7.13 (2H, m).

Production Example 431-(tert-Butoxycarbonyl)-4-fluoro-4-(2-fluorophenoxymethyl)piperidine

The title compound (158 mg, 100% yield) was obtained in the same manneras Example 41 from 162 mg of 2-fluorophenol and 150 mg of1-(tert-butoxycarbonyl)-4-fluoro-4-(methanesulfonyloxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47 (9H, s), 1.50-2.02 (6H, m),3.04-3.20 (2H, m), 4.03 (2H, d, J=17.2 Hz), 6.83-7.11 (4H, m).

Production Example 441-(tert-Butoxycarbonyl)-4-hydroxy-4-(2-methylphenoxymethyl)piperidine

After dissolving 120 mg of6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2.5]octane in 10 ml ofN,N-dimethylformamide, 67 mg of 2-methylphenol and 86 mg of potassiumcarbonate were added and the mixture was stirred at 150° C. for 5 hours.After cooling it to room temperature, water was added and extraction wasperformed with ethyl acetate. The extract was dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain thetitle compound (156 mg, 86% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47 (9H, s), 1.60-1.68 (2H, m),1.74-1.78 (2H, m), 2.25 (3H, s), 3.23 (2H, t, J=11.6 Hz), 3.81 (2H, s),3.92 (2H, br s), 6.78-6.81 (1H, m), 6.89 (1H, td, J=7.6, 1.2 Hz),7.14-7.18 (2H, m).

Production Example 451-(tert-Butoxycarbonyl)-4-(2-fluorophenoxymethyl)-4-hydroxypiperidine

The title compound (489 mg, 100% yield) was obtained in the same manneras Production Example 44 from 302 mg of6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2.5]octane and 175 mg of2-fluorophenol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.62 (2H, td, J=17.6, 4.4Hz), 1.75-1.80 (2H, m), 3.18-3.30 (2H, m), 3.86 (2H, s), 3.86-3.99 (2H,m), 6.82-6.96 (2H, m), 6.98-7.12 (2H, m).

Production Example 467-(tert-Butoxycarbonyl)-2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane

After dissolving 148 mg of 2-fluorophenol in 10 mg of dimethylformamide,53 mg of sodium hydride (70% suspension in oil) was added, the mixturewas stirred at 80° C. for 30 minutes, a solution of 148 mg of7-(tert-butoxycarbonyl)-2-methanesulfonyloxy-7-azaspiro[3.5]nonane inN,N-dimethylformamide (7 ml) was added and the mixture was stirred at80° C. for two nights. After cooling it to room temperature, water wasadded and extraction was performed with ethyl acetate. The organic layerwas washed with a 1N sodium hydroxide solution and then dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure to obtain the title compound (163 mg, 100% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45 (9H, s), 1.53-1.62 (4H, m),1.99-2.05 (1H, m), 2.02 (1H, dd, J=10.8, 6.4 Hz), 2.39-2.44 (2H, m),3.31-3.33 (2H, m), 3.36-3.39 (2H, m), 4.72 (1H, quintet, J=6.7 Hz), 6.79(1H, td, J=8.4, 1.6 Hz), 6.88 (1H tdd, J=8.0, 4.8, 1.8 Hz), 6.99-7.05(1H, m), 7.07 (1H, ddd, J=11.4, 8.0, 1.6 Hz).

Production Example 47anti-(E)-3-Benzyl-9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonane

30 ml of tetrahydrofuran was cooled to −78° C., 4.45 ml ofn-butyllithium (2.6 M, n-hexane solution) was added thereto, and 1.45 mlof 1-bromo-2-fluorobenzene was added dropwise while stirring. After 15minutes, a solution of 2.40 g of(anti-3-benzyl-3-azabicyclo[3.3.1]non-9-yl)acetaldehyde intetrahydrofuran (10 ml) was added dropwise. After another hour, waterwas added to the reaction solution and extraction was performed withethyl acetate. The organic layer was washed with water and saturatedbrine in that order and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure.

This was dissolved in 50 ml of toluene, and then 4.23 g ofp-toluenesulfonic acid monohydrate was added and the mixture was heatedto reflux for 2 hours. Aqueous sodium carbonate solution was added tothe reaction solution and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (2.61 g, 88% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.49-1.62 (3H, m), 1.81-1.86 (2H, m),1.87-2.00 (2H, m), 2.30-2.36 (2H, m), 2.38-2.43 (1H, m), 2.67-2.81 (1H,m), 2.98-3.03 (2H, m), 3.42 (2H, s), 6.56-6.66 (2H, m), 6.99-7.36 (8H,m), 7.48 (1H, dt, J=7.6, 2.0 Hz).

Production Example 48anti-(E)-9-[2-(2-Fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonanehydrochloride

The title compound (1.12 g, 51% yield) was obtained in the same manneras Production Example 29 from 2.61 g ofanti-(E)-3-benzyl-9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonane.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60-1.84 (3H, m), 1.98-2.11 (2H, m),2.14 (2H, br s), 2.23-2.38 (1H, m), 2.64 (1H, br d, J=6.0 Hz), 3.31-3.42(2H, m), 3.53-3.61 (2H, m), 6.48 (1H, dd, J=16.0, 6.8 Hz), 6.65 (1H, d,J=16.0 Hz), 7.05 (1H, ddd, J=10.8, 8.0, 1.2 Hz), 7.11 (1H, dt, J=8.0,1.2 Hz), 7.19-7.25 (1H, m), 7.45 (1H, dt, J=8.0, 1.2 Hz), 8.56 (1H, brs), 10.14 (1H, br s).

Production Example 49 4-[2-(3-Fluoro-2-thienyl)ethyl]piperidine

After dissolving 365 mg of 3-fluorothiophene-2-methanol in 5 ml oftoluene, 0.27 ml of thionyl chloride was added while stirring on ice andthe mixture was stirred for 1 hour. Saturated aqueous sodium bicarbonatesolution was added to the reaction solution and extraction was performedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. After adding 5 ml of toluene tothe residue, 647 mg of triphenylphosphine was added and the mixture washeated to reflux overnight. Ethyl acetate was added and the insolubleportion was filtered. After dissolving this in 3 ml ofN,N-dimethylformamide, 154 mg of potassium tert-butoxide was added, asolution of 270 mg of 1-benzylpiperidine-4-carboxaldehyde inN,N-dimethylformamide (1 ml) was added while stirring on ice, and themixture was stirred for 1 hour. Water was added to the reactionsolution, and extraction was performed with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by NH silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain1-benzyl-4-[2-(3-fluoro-2-thienyl)vinyl]piperidine. After dissolvingthis in 5 ml of methanol, 320 mg of 10% palladium-carbon (hydrous) and332 mg of ammonium formate were added and the mixture was heated andstirred at 50° C. for 1.5 hours. The insoluble portion was filtered off,water was added to the filtrate and extraction was performed with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was dissolved in 3 ml of1,2-dichloroethane, and then 0.12 ml of 1-chloroethyl chloroformate wasadded while stirring on ice and the mixture was heated to reflux for 1hour. The solvent was distilled off under reduced pressure, 3 ml ofmethanol was added to the residue and heating to reflux was continuedfor 30 minutes. The solvent was distilled off under reduced pressure, a1N sodium hydroxide solution was added and extraction was performed withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: methanol/ethyl acetate) toobtain the title compound (150 mg, 29% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.07-1.18 (2H, m), 1.35-1.47 (1H, m),1.52-1.66 (2H, m), 1.67-1.76 (2H, m), 2.53-2.62 (2H, m), 2.74 (2H, td,J=7.8, 0.8 Hz), 3.03-3.10 (2H, m), 6.73 (1H, dd, J=5.4, 1.0 Hz), 6.97(1H, dd, J=5.4, 4.0 Hz).

Production Example 50 3-Bromothiophene-2-carboxaldehyde dimethylacetal

After dissolving 5.97 g of 3-bromothiophene-2-carboxaldehyde in 90 ml ofdichloromethane, a mixture of 8.0 g of montmorillonite K-10 and 120 mlof trimethyl orthoformate was added while stirring and the mixture wasstirred at room temperature for 1 hour. The reaction mixture wasfiltered and then the solvent was distilled off under reduced pressureto obtain the title compound (7.21 g, 97% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 3.39 (6H, s), 5.62 (1H, s), 6.97 (1H, d,J=5.4 Hz), 7.30 (1H, d, J=5.4 Hz).

Production Example 51 3-Fluorothiophene-2-carboxaldehyde

After dissolving 5.54 g of 3-bromothiophene-2-carboxaldehydedimethylacetal in 120 ml of diethyl ether, the solution was cooled to−78° C. Next, 9.3 ml of n-butyllithium (2.66 M, n-hexane solution) wasadded dropwise while stirring at below −67° C. After 30 minutes, asolution of 8.10 g of N-fluorobenzenesulfonimide in tetrahydrofuran (20ml) was added dropwise, and the temperature was raised to roomtemperature. Water was added to the reaction solution, and extractionwas performed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue wasdissolved in 10 ml of acetone, 10 ml of 5N hydrochloric acid was addedand the mixture was stirred at room temperature for 20 minutes. A 5Nsodium hydroxide solution was added to the reaction solution forneutralization and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (1.86 g,61% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 6.91 (1H, d, J=5.4 Hz), 7.65 (1H, ddd,J=5.4, 4.2, 1.2 Hz), 10.04 (1H, d, J=1.2 Hz).

Production Example 52 3-Fluorothiophene-2-methanol

After dissolving 1.86 g of 3-fluorothiophene-2-carboxaldehyde in 30 mlof methanol, 541 mg of sodium borohydride was added while stirring onice and the mixture was stirred for 30 minutes. Water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (1.60 g,85% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.75 (1H, t, J=5.2 Hz), 4.78 (2H, d,J=5.2 Hz), 6.78 (1H, dd, J=5.4, 0.8 Hz), 7.16 (1H, dd, J=5.4, 4.0 Hz).

Production Example 53 2-Fluorothiophene-3-carboxaldehyde

After dissolving 2.55 ml of N,N,N′-trimethylethylenediamine in 60 ml ofdiethyl ether, the solution was cooled to −78° C. Next, 7.58 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise whilestirring at below −60° C. After 20 minutes, a solution of 2.00 g of3-thiophenecarboxaldehyde in diethyl ether (5 ml) was added dropwise atbelow −60° C. The mixture was stirred for 15 minutes, and then 7.58 mlof n-butyllithium (2.6 M, n-hexane solution) was added dropwise at below−60° C. After 10 minutes, the temperature was raised to room temperatureand the mixture was stirred for 2 hours. The reaction solution wascooled to −78° C., and a solution of 6.21 g ofN-fluorobenzenesulfonimide in tetrahydrofuran (20 ml) was added dropwiseat below −60° C. After the dropwise addition, the reaction solution wasstirred at room temperature for 1.5 hours. Water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with water and saturated brine, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (138 mg, 6% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 6.66-6.71 (1H, m), 7.08-7.13 (1H, m),9.97 (1H, s).

Production Example 54 3-Hydroxy-4-hydroxymethyl-[1,2,5]thiadiazole

After dissolving 1.00 g of4-tert-butoxymethyl-3-hydroxy-[1,2,5]thiadiazole in 6 ml ofdichloromethane, 6 ml of trifluoroacetic acid was added and the mixturewas stirred at room temperature for 1.5 hours. The reaction solution wasconcentrated, and n-hexane was added to the residue and then distilledoff under reduced pressure. After further addition of n-hexane to theresidue, the mixture was filtered to obtain the title compound (523 mg,75% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 4.48 (2H, s).

Production Example 551-(tert-Butoxycarbonyl)-4-[2-(dimethylamino)phenoxymethyl]piperidine

After dissolving 400 mg of1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml oftetrahydrofuran, 0.33 ml of 37% formalin, 0.08 ml of acetic acid and 827mg of sodium triacetoxyborohydride were added and the mixture wasstirred at room temperature for 2.5 hours. Next, 0.33 ml of 37% formalinand 827 mg of sodium triacetoxyborohydride were added to the reactionsolution and stirring was continued overnight at room temperature. Afteradding aqueous sodium carbonate solution to the reaction solution,extraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, and then filtered with NH silica gel. The solvent was distilledoff under reduced pressure to obtain the title compound (447 mg, 100%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.36 (2H, m), 1.47 (9H, s),1.84-1.92 (2H, m), 2.03-2.15 (1H, m), 2.50-2.84 (8H, m), 3.85 (2H, d,J=6.8 Hz), 4.08-4.26 (2H, m), 6.80-6.96 (4H, m).

Production Example 56 2-Chloro-6-methoxypyrazine

After dissolving 7.99 g of 2,6-dichloropyrazine in 100 ml oftetrahydrofuran, 11.3 ml of a 28% sodium methoxide-methanol solution wasadded dropwise while stirring at room temperature, and stirring wascontinued overnight. Water was added to the reaction solution, andextraction was performed with n-hexane. The organic layer was washedwith water and saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressureto obtain the title compound (6.96 g, 90% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 3.98 (3H, s), 8.12 (1H, d, J=0.4 Hz),8.13 (1H, d, J=0.4 Hz).

Production Example 571-(tert-Butoxycarbonyl)-4-[2-(3-methylthioureido)phenoxymethyl]piperidine

After dissolving 400 mg of1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml oftetrahydrofuran, 124 mg of methyl isothiocyanate was added and themixture was heated to reflux for 3.5 hours. The reaction solution wasfiltered with NH silica gel and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (537 mg, 100% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.16-1.28 (2H, m), 1.46 (9H, s),1.79-1.87 (2H, m), 1.95-2.06 (1H, m), 2.70-2.82 (2H, m), 3.15 (3H, d,J=4.8 Hz), 3.82 (2H, d, J=5.6 Hz), 4.10-4.24 (2H, m), 6.09-6.16 (1H, m),6.94-7.02 (2H, m), 7.20-7.34 (2H, m), 7.47 (1H, br s).

Production Example 581-(tert-Butoxycarbonyl)-4-[2-(3-methylureido)phenoxymethyl]piperidine

After dissolving 400 mg of1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml oftetrahydrofuran, 458 mg of methyl isocyanate was added and the mixturewas stirred overnight at room temperature. Ammonia water was added tothe reaction solution and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine and driedover anhydrous magnesium sulfate, and then filtered with NH silica gel.The solvent was distilled off under reduced pressure to obtain the titlecompound (469 mg, 99% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.22-1.35 (2H, m), 1.47 (9H, s),1.76-1.84 (2H, m), 1.93-2.05 (1H, m), 2.68-2.81 (2H, m), 2.86 (3H, d,J=4.8 Hz), 3.86 (2H, d, J=6.4 Hz), 4.10-4.24 (2H, m), 4.66-4.75 (1H, m),6.62 (1H, br s), 6.84 (1H, dd, J=8.0, 1.6 Hz), 6.92-7.02 (2H, m), 7.90(1H, dd, J=7.6, 2.0 Hz).

Production Example 59 4-Fluorothiophene-3-carboxaldehyde

After dissolving 18.38 g of 4-bromothiophene-3-carboxaldehydedimethylacetal in 400 ml of diethyl ether, the solution was cooled to−78° C. Next, 32.81 ml of n-butyllithium (2.6 M, n-hexane solution) wasadded dropwise while stirring at below −65° C. After 40 minutes, asolution of 26.94 g of N-fluorobenzenesulfonimide in tetrahydrofuran(100 ml) was added dropwise, and the temperature was gradually raised to0° C. The mixture was stirred at 0° C. for 45 minutes and then ice waterwas added to the reaction solution and extraction was performed withethyl acetate. The organic layer was washed with water and brine, andthe solvent was distilled off under reduced pressure. The residue wasdissolved in 50 ml of acetone, and then 50 ml of 5N hydrochloric acidwas added and the mixture was allowed to stand at room temperature for1.5 hours. A 5N sodium hydroxide solution was added to the reactionsolution for neutralization, and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate) to obtainthe title compound (6.02 g, 63% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 6.82 (1H, dd, J=4.0, 1.2 Hz), 8.01 (1H,t, J=4.0 Hz), 9.88 (1H, s).

Production Example 60 4-tert-Butoxymethyl-3-hydroxy-[1.2.5]thiadiazole

After dissolving 8.17 g of 2-amino-3-(tert-butoxy)propionamide in 150 mlof dichloromethane, 16.37 ml of triethylamine was added and the solutionwas cooled to −78° C., and then 4.10 ml of thionyl chloride was addeddropwise while stirring at below −50° C. After stirring for 30 minutes,the temperature was raised to room temperature and stirring wascontinued overnight. Water was added to the reaction solution, andextraction was performed with dichloromethane. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andfiltered with silica gel. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (1.98 g, 21% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35 (9H, s), 4.83 (2H, s), 9.22 (1H, brs).

Production Example 61 2-(4-Fluoro-3-thienyl)-1-(4-pyridyl)ethanone

After dissolving 19.6 g of [(phenylamino)-(4-pyridylmethyl)]phosphonicacid diphenyl ester [CAS No. 3360-72-3] in 115 ml oftetrahydrofuran-2-propanol (4:1), 6.02 g of4-fluorothiophene-3-carboxaldehyde and 19.61 g of anhydrous cesiumcarbonate were added and the mixture was stirred overnight at roomtemperature. Next, 90 ml of 5N hydrochloric acid was added to thereaction mixture and the mixture was stirred at room temperature for 6hours. After adding a 5N sodium hydroxide solution to the reactionsolution, extraction was performed with ethyl acetate. The organic layerwas washed with water and saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate). The obtained solid was washed withn-hexane to obtain the title compound (3.66 g, 36% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 4.21 (2H, s), 6.76 (1H, d, J=3.6 Hz),7.09 (1H, t, J=3.6 Hz), 7.76-7.80 (2H, m), 8.80-8.86 (2H, m).

Production Example 621-(tert-Butoxycarbonyl)-4-(2-fluorobenzylthio)piperidine

After dissolving 1.70 g of 1-(tert-butoxycarbonyl)-4-mercaptopiperidinein a mixture of 8 ml ethanol/8 ml 2N sodium hydroxide, 1.05 ml of2-fluorobenzyl bromide was added and the mixture was stirred overnightat room temperature. Water was added to the reaction solution, andextraction was performed with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (1.72 g, 68%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.58 (2H, m), 1.45 (9H, s),1.86-1.95 (2H, m), 2.68-2.77 (1H, m), 2.83-2.94 (2H, m), 3.78 (2H, s),3.85-4.00 (2H, m), 7.02 (1H, ddd, J=9.6, 8.0, 1.2 Hz), 7.09 (1H, td,J=8.0, 1.2 Hz), 7.19-7.26 (1H, m), 7.34 (1H, td, J=8.0, 2.0 Hz).

Production Example 631-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-(2-fluorophenyl)propanone

After suspending 207 mg of sodium hydride (70% suspension in oil) in 4ml of N,N-dimethylformamide, a solution of 1.51 g of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone inN,N-dimethylformamide (6 ml) was added, the mixture was stirred at roomtemperature for 30 minutes, and then 0.32 ml of methyl iodide was addedand stirring was continued for 30 minutes. Water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (1.16 g, 74%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.37 (3H, d, J=7.0 Hz), 1.40-1.60 (3H,m), 1.43 (9H, s), 1.77-1.86 (1H, m), 2.48-2.76 (3H, m), 3.95-4.15 (2H,m), 4.26 (1H, q, J=7.0 Hz), 7.06 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.11(1H, dd, J=7.6, 1.2 Hz), 7.16 (1H, td, J=7.6, 2.0 Hz), 7.21-7.27 (1H,m).

Production Example 64cis-1-Benzyl-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine

After dissolving 1.49 g ofcis-1-benzyl-4-hydroxy-3-(p-toluenesulfonyloxymethyl)piperidine in 8 mlof N,N-dimethylformamide, 0.71 ml of 2-fluorophenol and 1.22 g ofanhydrous potassium carbonate were added and the mixture was stirred at100° C. for 50 minutes. Water was added to the reaction mixture, andextraction was performed with ethyl acetate. The organic layer waswashed with a 5N sodium hydroxide solution, water and saturated brine inthat order and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (402 mg, 32% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.74-1.89 (2H, m), 2.28-2.36 (1H, m),2.45-2.60 (4H, m), 3.51 (1H, d, J=13.2 Hz), 3.55 (1H, d, J=13.2 Hz),4.06-4.25 (3H, m), 6.85-6.92 (1H, m), 6.96 (1H, dt, J=8.4, 1.6 Hz),7.00-7.08 (2H, m), 7.20-7.33 (5H, m).

Production Example 65trans-1-Benzyl-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine

The title compound (326 mg, 61% yield) was obtained in the same manneras Production Example 64 from 0.65 g oftrans-1-benzyl-4-hydroxy-3-(p-toluenesulfonyloxymethyl)piperidine and0.31 ml of 2-fluorophenol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.62-1.74 (1H, m), 1.92-2.21 (4H, m),2.84-2.91 (1H, m), 2.93-2.99 (1H, m), 3.50 (1H, d, J=13.2 Hz), 3.54 (1H,d, J=13.2 Hz), 3.64 (1H, dt, J=10.0, 4.8 Hz), 4.05 (1H, dd, J=6.0, 9.6Hz), 4.11 (1H, dd, J=5.6, 9.6 Hz), 6.85-6.98 (2H, m), 7.00-7.08 (2H, m),7.21-7.34 (5H, m).

Production Example 661-(tert-Butoxycarbonyl)-4-methyl-4-(2-methylphenoxymethyl)piperidine

After dissolving 541 mg of 2-methylphenol in 10 ml ofN,N-dimethylformamide, 171 mg of sodium hydride (70% suspension in oil),1.00 g of1-(tert-butoxycarbonyl)-4-methyl-4-(methanesulfonyloxymethyl)piperidineand tetra n-butylammonium iodide (catalytic amount) were added and themixture was stirred at 120° C. overnight. Water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (816 mg, 78% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.14 (3H, s), 1.40-1.48 (2H, m), 1.46(9H, s), 1.60-1.69 (2H, m), 2.23 (3H, s), 3.21 (2H, ddd, J=13.6, 10.0,3.6 Hz), 3.61-3.74 (2H, m), 3.67 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.84(1H, dt, J=7.6, 0.8 Hz), 7.10-7.17 (2H, m).

Production Example 671-(tert-Butoxycarbonyl)-4-(2-chlorophenoxymethyl)-4-methylpiperidine

The title compound (810 mg, 72% yield) was obtained in the same manneras Production Example 66 from 0.40 ml of 2-chlorophenol and 1.00 g of1-(tert-butoxycarbonyl)-4-methyl-4-(methanesulfonyloxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.16 (3H, s), 1.43-1.51 (2H, m), 1.46(9H, s), 1.61-1.69 (2H, m), 3.22 (2H, ddd, J=13.6, 9.6, 3.6 Hz),3.66-3.76 (2H, m), 3.72 (2H, s), 6.85-6.90 (1H, m), 7.16-7.21 (2H, m),7.32-7.36 (1H, m).

Production Example 681-(tert-Butoxycarbonyl)-4-(2-methoxyphenoxymethyl)-4-methylpiperidine

The title compound (293 mg, 27% yield) was obtained in the same manneras Production Example 66 from 0.55 ml of 2-methoxyphenol and 1.00 g of1-(tert-butoxycarbonyl)-4-methyl-4-(methanesulfonyloxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.14 (3H, s), 1.40-1.48 (2H, m), 1.46(9H, s), 1.61-1.69 (2H, m), 3.21 (2H, ddd, J=13.6, 10.0, 3.6 Hz),3.62-3.72 (2H, m), 3.71 (2H, s), 3.83 (3H, s), 6.86-6.91 (4H, m).

Production Example 692-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrileand2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrile

After dissolving 1.3 ml of diisopropylamine in 20 ml of tetrahydrofuran,the solution was cooled to −78° C. Next, 5.8 ml of n-butyllithium (1.5M, n-hexane solution) was added dropwise while stirring at below −40°C., and stirring was continued for 40 minutes. A solution of 1.49 g of1-(tert-butoxycarbonyl)piperidine-4-acetonitrile in tetrahydrofuran (5ml) was added dropwise at below −60° C., the mixture was stirred for 1hour, and then 1.2 ml of 2-fluorobenzyl bromide was added and thetemperature was raised to room temperature. Saturated aqueous ammoniumchloride solution was added to the reaction solution, and extraction wasperformed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrile(1.21 g, 55% yield) and2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrile(1.02 g, 35% yield).

2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrile

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.53 (2H, m), 1.46 (9H, s),1.65-1.78 (2H, m), 1.88-1.96 (1H, m), 2.62-2.90 (4H, m), 3.04 (1H, dd,J=13.2, 5.6 Hz), 4.10-4.30 (2H, m), 7.02-7.15 (2H, m), 7.23-7.30 (2H,m).

2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrile

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.69 (3H, m), 1.46 (9H, s),1.97-2.05 (2H, m), 2.55-2.67 (2H, m), 2.81 (2H, d, J=14.0 Hz), 3.04 (2H,d, J=14.0 Hz), 4.15-4.32 (2H, m), 7.06 (2H, ddd, J=9.6, 7.6, 1.2 Hz),7.13 (2H, td, J=7.6, 1.2 Hz), 7.24-7.31 (2H, m), 7.36 (2H, td, J=7.6,1.6 Hz).

Production Example 701-(tert-Butoxycarbonyl)-4-[2-(methoxycarbonyl)phenoxymethyl]piperidine

After dissolving 300 mg of1-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)piperidine in 3 mlof N,N-dimethylformamide, 0.16 ml of methyl salicylate, 180 mg ofanhydrous potassium carbonate and tetra n-butylammonium iodide(catalytic amount) were added and the mixture was stirred at 100° C. for1.5 hours. Water was added to the reaction mixture, and extraction wasperformed with ethyl acetate. The organic layer was washed with waterand saturated brine and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (226 mg, 65% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.25-1.37 (2H, m), 1.47 (9H, s),1.83-1.90 (2H, m), 1.97-2.09 (1H, m), 2.68-2.84 (2H, m), 3.84-3.93 (5H,m), 4.08-4.26 (2H, m), 6.93 (1H, d, J=7.6 Hz), 6.97 (1H, t, J=7.6 Hz),7.41-7.47 (1H, m), 7.79 (1H, dd, J=7.6, 1.6 Hz).

Production Example 714-(2-Acetylphenoxymethyl)-1-(tert-butoxycarbonyl)piperidine

The title compound (220 mg, 66% yield) was obtained in the same manneras Production Example 70 from 300 mg of1-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)piperidine and 0.14ml of 2-hydroxyacetophenone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.26-1.39 (2H, m), 1.47 (9H, s),1.80-1.88 (2H, m), 1.98-2.10 (1H, m), 2.62 (3H, s), 2.68-2.84 (2H, m),3.92 (2H, d, J=6.4 Hz), 4.06-4.28 (2H, m), 6.93 (1H, d, J=7.6 Hz),6.97-7.02 (1H, m), 7.41-7.47 (1H, m), 7.70-7.74 (1H, m).

Production Example 721-(tert-Butoxycarbonyl)-4-(2-carbamoylphenoxymethyl)piperidine

The title compound (165 mg, 73% yield) was obtained in the same manneras Production Example 70 from 200 mg of1-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)piperidine and 112mg of salicylamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.38 (2H, m), 1.47 (9H, s),1.78-1.86 (2H, m), 1.99-2.12 (1H, m), 2.68-2.84 (2H, m), 4.00 (2H, d,J=6.4 Hz), 4.02-4.30 (2H, m), 5.87 (1H, br s), 6.97 (1H, d, J=8.4 Hz),7.05-7.12 (1H, m), 7.42-7.49 (1H, m), 7.66 (1H, br s), 8.20 (1H, dd,J=8.0, 1.6 Hz).

Production Example 731-(tert-Butoxycarbonyl)-4-(2-nitrophenoxymethyl)piperidine

The title compound (191 mg, 84% yield) was obtained in the same manneras Production Example 70 from 200 mg of1-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)piperidine and 114mg of 2-nitrophenol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.22-1.34 (2H, m), 1.47 (9H, s),1.81-1.90 (2H, m), 1.97-2.10 (1H, m), 2.66-2.84 (2H, m), 3.93 (2H, d,J=5.6 Hz), 4.06-4.28 (2H, m), 7.00-7.08 (2H, m), 7.49-7.55 (1H, m), 7.83(1H, dd, J=8.0, 1.6 Hz).

Production Example 741-(tert-Butoxycarbonyl)-4-[2-(acetylamino)phenoxymethyl]piperidine

After dissolving 400 mg of1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml oftetrahydrofuran, 0.15 ml of acetic anhydride and 0.24 ml oftriethylamine were added and the mixture was stirred overnight at roomtemperature. The reaction solution was filtered with silica gel and NHsilica gel. The solvent was distilled off under reduced pressure toobtain the title compound (459 mg, 100% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.36 (2H, m), 1.47 (9H, s),1.77-1.84 (2H, m), 1.97-2.09 (1H, m), 2.20 (3H, s), 2.68-2.84 (2H, m),3.89 (2H, d, J=6.4 Hz), 4.08-4.26 (2H, m), 6.85 (1H, dd, J=8.0, 1.2 Hz),6.93-7.05 (2H, m), 7.67 (1H, br s), 8.34 (1H, dd, J=8.0, 1.6 Hz).

Production Example 752-(2,3-Dihydrobenzofuran-7-yl)-1-(piperidin-4-yl)ethanone hydrochloride

The title compound (86 mg, 64% yield) was obtained in the same manner asProduction Example 29 from 159 mg of1-(1-benzylpiperidin-4-yl)-2-(2,3-dihydrobenzofuran-7-yl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.56-1.69 (2H, m), 1.92-2.01 (2H, m),2.75-2.93 (3H, m), 3.15 (2H, t, J=8.8 Hz), 3.20-3.35 (2H, m), 3.72 (2H,s), 4.45 (2H, t, J=8.8 Hz), 6.74 (1H, t, J=7.4 Hz), 6.87 (1H, d, J=7.4Hz), 7.10 (1H, dd, J=7.4, 1.2 Hz).

Production Example 762-[2-(Methylthio)phenyl]-1-(piperidin-4-yl)ethanone hydrochloride

The title compound (660 mg, 100% yield) was obtained in the same manneras Production Example 29 from 768 mg of1-(1-benzylpiperidin-4-yl)-2-[2-(methylthio)phenyl]ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.63-1.76 (2H, m), 1.98-2.06 (2H, m),2.40 (3H, s), 2.82-2.96 (3H, m), 3.22-3.31 (2H, m), 3.95 (2H, s),7.10-7.17 (2H, m), 7.23-7.32 (2H, m), 8.56-8.70 (1H, m), 8.86-9.02 (1H,m).

Production Example 771-(Piperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone hydrochloride

After dissolving 1.30 g of1-(1-benzylpiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone in 10ml of 1,2-dichloroethane, 0.58 ml of 1-chloroethyl chloroformate wasadded while stirring at room temperature and the mixture was heated toreflux for 1 hour. The solvent was distilled off under reduced pressure,10 ml of methanol was added to the residue and heating to reflux wascontinued for 30 minutes. The solvent was distilled off under reducedpressure, ethyl acetate/n-hexane was added to the residue and theprecipitate was filtered out to obtain the title compound (916 mg, 83%yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.61-1.73 (2H, m), 1.98-2.06 (2H, m),2.83-2.98 (3H, m), 3.24-3.36 (2H, m), 4.12 (2H, d, J=1.2 Hz), 7.37 (1H,d, J=7.6 Hz), 7.47 (1H, t, J=7.6 Hz), 7.62 (1H, t, J=7.6 Hz), 7.69 (1H,d, J=7.6 Hz), 8.50-8.68 (1H, m), 8.84-8.98 (1H, m).

Production Example 781-(Piperidin-4-yl)-2-[2-(trifluoromethoxy)phenyl]ethanone hydrochloride

The title compound (750 mg, 78% yield) was obtained in the same manneras Production Example 29 from 1.12 g of1-(1-benzylpiperidin-4-yl)-2-[2-(trifluoromethoxy)phenyl]ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.61-1.73 (2H, m), 1.98-2.06 (2H, m),2.82-2.98 (3H, m), 3.24-3.34 (2H, m), 3.99 (2H, s), 7.30-7.43 (4H, m).

Production Example 79 2-(2-Ethoxyphenyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (339 mg, 69% yield) was obtained in the same manneras Production Example 29 from 581 mg of1-(1-benzylpiperidin-4-yl)-2-(2-ethoxyphenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.26 (3H, t, J=6.8 Hz), 1.62-1.74 (2H,m), 1.94-2.02 (2H, m), 2.77-2.97 (3H, m), 3.22-3.30 (2H, m), 3.75 (2H,s), 3.96 (2H, q, J=6.8 Hz), 6.86 (1H, td, J=8.0, 1.2 Hz), 6.92 (1H, dd,J=8.0, 1.2 Hz), 7.10 (1H, dd, J=8.0, 1.6 Hz), 7.20 (1H, ddd, J=9.2, 8.0,1.6 Hz), 8.58 (1H, br s), 8.86 (1H, br s).

Production Example 80 1-(Piperidin-4-yl)-2-(2-n-propoxyphenyl)ethanonehydrochloride

The title compound (390 mg, 58% yield) was obtained in the same manneras Production Example 29 from 799 mg of1-(1-benzylpiperidin-4-yl)-2-(2-n-propoxyphenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 0.94 (3H, t, J=7.2 Hz), 1.60-1.72 (4H,m), 1.92-2.01 (2H, m), 2.75-2.96 (3H, m), 3.32-3.30 (2H, m), 3.76 (2H,s), 3.87 (2H, t, J=6.4 Hz), 6.86 (1H, td, J=7.6, 1.2 Hz), 6.92 (1H, dd,J=7.6, 1.2 Hz), 7.10 (1H, dd, J=7.6, 1.6 Hz), 7.20 (1H, ddd, J=9.2, 7.6,1.6 Hz), 8.56 (1H, br s), 8.85 (1H, br s).

Production Example 81 2-(1-Naphthyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (425 mg, 46% yield) was obtained in the same manneras Production Example 29 from 1.00 g of1-(1-benzylpiperidin-4-yl)-2-(1-naphthyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.65-1.77 (2H, m), 2.02-2.10 (2H, m),2.85-3.02 (3H, m), 3.23-3.32 (2H, m), 4.37 (2H, s), 7.37 (1H, d, J=6.4Hz), 7.42-7.53 (3H, m), 7.76-7.81 (1H, m), 7.83 (1H, d, J=8.0 Hz),7.89-7.94 (1H, m), 8.67 (1H, br s), 8.96 (1H, br s).

Production Example 82 2-(2-Biphenyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (642 mg, 52% yield) was obtained in the same manneras Production Example 29 from 1.45 g of1-(1-benzylpiperidin-4-yl)-2-(2-biphenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.38-1.51 (2H, m), 1.66-1.76 (2H, m),2.53-2.62 (1H, m), 2.74-2.85 (2H, m), 3.11-3.20 (2H, m), 3.84 (2H, s),7.14-7.24 (4H, m), 7.29-7.43 (5H, m), 8.37 (1H, br s), 8.71 (1H, br s).

Production Example 83 2-(2-Bromophenyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (942 mg, 68% yield) was obtained in the same manneras Production Example 29 from 1.63 g of1-(1-benzylpiperidin-4-yl)-2-(2-bromophenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.65-1.77 (2H, m), 2.00-2.09 (2H, m),2.84-2.98 (3H, m), 3.23-3.32 (2H, m), 4.04 (2H, s), 7.20 (1H, td, J=7.6,2.0 Hz), 7.27-7.36 (2H, m), 7.58 (1H, dd, J=7.6, 1.2 Hz), 8.64 (1H, brs), 8.94 (1H, br s).

Production Example 84trans-2-(2-Fluorophenyl)-1-(3-methylpiperidin-4-yl)ethanonehydrochloride

The title compound (496 mg, 87% yield) was obtained in the same manneras Production Example 29 from 0.69 g oftrans-1-(1-benzyl-3-methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 0.81 (3H, d, J=6.8 Hz), 1.51-1.64 (1H,m), 1.97-2.12 (2H, m), 2.52-2.68 (2H, m), 2.79-2.91 (1H, m), 3.15-3.22(1H, m), 3.28-3.40 (1H, m), 3.86 (1H, d, J=18.0 Hz), 4.03 (1H, d, J=18.0Hz), 7.10-7.20 (2H, m), 7.24-7.35 (2H, m), 8.64-8.84 (1H, m), 8.95-9.12(1H, m).

Production Example 853,3-Dimethoxy-4-[2-(2-fluorophenyl)ethyl]piperidine hydrochloride

The title compound (1.01 g, 86% yield) was obtained in the same manneras Production Example 29 from 1.26 g of1-benzyl-3-methoxy-4-[2-(2-fluorophenyl)ethyl]-1,2,5,6-tetrahydropyridine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.58-1.97 (5H, m), 2.53-2.60 (1H, m),2.66-2.76 (1H, m), 2.78-2.86 (1H, m), 2.94-3.02 (2H, m), 3.01 (3H, s),3.13 (3H, s), 3.17-3.24 (1H, m), 7.09-7.17 (2H, m), 7.22-7.28 (1H, m),7.34 (1H, td, J=7.6, 1.6 Hz), 8.36-8.52 (1H, m), 9.30-9.43 (1H, m).

Production Example 862-[2-Fluoro-6-(trifluoromethyl)phenyl]-1-(piperidin-4-yl)ethanone

After dissolving 136 mg of1-(1-benzylpiperidin-4-yl)-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethanonein 3 ml of 1,2-dichloroethane, 0.06 ml of 1-chloroethyl chloroformatewas added and the mixture was stirred at room temperature for 5 minutesand then heated to reflux for 45 minutes. The solvent was distilled offunder reduced pressure, 10 ml of methanol was added to the residue andheating to reflux was continued for 30 minutes. The solvent wasdistilled off under reduced pressure, ammonia water was added to theresidue and extraction was performed with dichloromethane. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by NH silica gel columnchromatography (solvent: ethyl acetate/methanol) to obtain the titlecompound (45 mg, 43% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.56-1.67 (2H, m), 1.87-1.94 (2H, m),2.58-2.72 (3H, m), 3.12-3.20 (2H, m), 3.99 (2H, s), 7.25 (1H, t, J=8.8Hz), 7.33-7.40 (1H, m), 7.45 (1H, d, J=8.0 Hz).

Production Example 87 2-(3-Methyl-2-thienyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (624 mg, 89% yield) was obtained in the same manneras Production Example 29 from 858 mg of1-(1-benzylpiperidin-4-yl)-2-(3-methyl-2-thienyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.59-1.71 (2H, m), 1.95-2.02 (2H, m),2.06 (3H, s), 2.79-2.95 (3H, m), 3.19-3.30 (2H, m), 4.02 (2H, s), 6.84(1H, d, J=5.2 Hz), 7.27 (1H, d, J=5.2 Hz), 8.61 (1H, br s), 8.90 (1H, brs).

Production Example 88 2-(4-Fluoro-3-thienyl)-1-(piperidin-4-yl)ethanonehydrochloride

The title compound (977 mg, 93% yield) was obtained in the same manneras Production Example 29 from 1.26 g of1-(1-benzylpiperidin-4-yl)-2-(4-fluoro-3-thienyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.61-1.73 (2H, m), 1.97-2.05 (2H, m),2.79-2.96 (3H, m), 3.22-3.30 (2H, m), 3.85 (2H, s), 7.15 (1H, d, J=3.6Hz), 7.31 (1H, t J=3.6 Hz), 8.73 (1H, br s), 9.01 (1H, br s).

Production Example 89 5-Chloro-3-methoxypyrazine-2-carboxaldehydedimethylacetal

The title compound (3.34 g, 88% yield) was obtained in the same manneras Production Example 50 from 3.01 g of5-chloro-3-methoxypyrazine-2-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 3.44 (6H, s), 4.03 (3H, s), 5.63 (1H,s), 8.17 (1H, s).

Production Example 90 4-Bromothiophene-3-carboxaldehyde dimethylacetal

The title compound (18.38 g, 100% yield) was obtained in the same manneras Production Example 50 from 14.78 g of4-bromothiophene-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 3.34 (6H, s), 5.41 (1H, d, J=0.8 Hz),7.26 (1H, d, J=3.6 Hz), 7.43 (1H, dd, J=3.6, 0.8 Hz).

Production Example 911-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-[2-(3-pyridyl)phenyl]ethanone

After dissolving 575 mg of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-bromophenyl)ethanone in10 ml of N,N-dimethylformamide, there were added 489 mg of2-(3-pyridyl)-1,3,2-dioxaborinane, 173 mg oftetrakis(triphenylphosphine) palladium(0) and 1.47 g of anhydrous cesiumcarbonate, and the mixture was stirred at 100° C. for 2 hours under anitrogen atmosphere. Water was added to the reaction mixture, andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (379 mg, 66% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.32-1.47 (2H, m), 1.44 (9H, s),1.55-1.66 (2H, m), 2.33 (1H, dt, J=11.2, 3.6 Hz), 2.60-2.74 (2H, m),3.73 (2H, s), 3.92-4.12 (2H, m), 7.16-7.41 (5H, m), 7.53-7.58 (1H, m),8.49 (1H, d, J=1.2 Hz), 8.59 (1H, dd, J=4.8, 1.6 Hz).

Production Example 92 2-(3-Methyl-2-thienyl)-1-(4-pyridyl)ethanone

The title compound (1.69 g, 78% yield) was obtained in the same manneras Production Example 61 from 4.16 g of[(phenylamino)-(4-pyridylmethyl)]phosphonic acid diphenyl ester and 1.19ml of 3-methyl-2-thiophenecarboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.18 (3H, s), 4.37 (2H, s), 6.84 (1H, d,J=5.2 Hz), 7.14 (1H, d, J=5.2 Hz), 7.74-7.78 (2H, m), 8.78-8.84 (2H, m).

Production Example 93 Methyl 3-methoxy-6-methylpyrazine-2-carboxylate

After dissolving 300 mg of methyl6-bromo-3-methoxypyrazine-2-carboxylate in 10 ml of tetrahydrofuran, 32mg of [1,3-bis(diphenylphosphino)propane]dichloronickel (II) was added,a solution of 0.73 ml of dimethyl zinc in toluene (2.0 M) was addeddropwise under a nitrogen atmosphere and the mixture was stirred at roomtemperature for 3 hours. Saturated aqueous ammonium chloride solutionand aqueous sodium carbonate solution were added to the reactionsolution in that order, and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (161 mg, 73% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.54 (3H, d, J=0.4 Hz), 3.98 (3H, s),4.03 (3H, s), 8.13 (1H, d, J=0.4 Hz).

Production Example 94N-methoxy-N-methyl-1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxamide

After dissolving 2.19 g of1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid in 30 ml ofdichloromethane, 2.16 g of 1,1′-carbonyldiimidazole was added and themixture was stirred at room temperature for 1.5 hours. Next, 1.30 g ofN-methyl-O-methylhydroxylamine hydrochloride was added and the mixturewas stirred overnight at room temperature. Water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with aqueous sodium carbonate solution, waterand saturated brine in that order and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (2.33 g, 90%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.93-2.14 (4H, m),3.04-3.18 (2H, m), 3.23 (3H, s), 3.72 (3H, s), 3.86-4.08 (2H, m).

Production Example 951-(tert-Butoxycarbonyl)-4-[2-(methanesulfonylamino)phenoxymethyl]piperidine

After dissolving 400 mg of1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml oftetrahydrofuran, 0.24 ml of triethylamine and 0.12 ml of methanesulfonylchloride were added and the mixture was stirred overnight at roomtemperature. Next, 0.24 ml of triethylamine and 0.12 ml ofmethanesulfonyl chloride were added to the reaction solution andstirring was continued at room temperature for 2 hours. The reactionsolution was filtered with silica gel and NH silica gel, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (447 mg, 90% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.32 (2H, m), 1.47 (9H, s),1.78-1.85 (2H, m), 1.95-2.06 (1H, m), 2.70-2.83 (2H, m), 2.96 (3H, s),3.87 (2H, d, J=6.8 Hz), 4.10-4.26 (2H, m), 6.74 (1H, br s), 6.90 (1H,dd, J=8.4, 1.2 Hz), 6.95-7.03 (1H, m), 7.10-7.15 (1H, m), 7.53 (1H, dd,J=8.0, 1.6 Hz).

Production Example 961-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-(2-bromophenyl)ethanone

After dissolving 525 mg of 2-(2-bromophenyl)-1-(piperidin-4-yl)ethanonehydrochloride in 8 ml of a 1N sodium hydroxide solution, a solution of431 mg of di-tert-butyl-dicarbonate in tetrahydrofuran (8 ml) was addedand the mixture was stirred at room temperature for 3 hours. Water wasadded to the reaction solution, and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate) to obtainthe title compound (675 mg, 94% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45 (9H, s), 1.56-1.67 (2H, m),1.82-1.92 (2H, m), 2.60-2.68 (1H, m), 2.73-2.85 (2H, m), 3.92 (2H, s),4.03-4.18 (2H, m), 7.13 (1H, dt, J=8.0, 1.6 Hz), 7.18 (1H, dd, J=8.0,1.6 Hz), 7.27 (1H, dt, J=8.0, 1.2 Hz), 7.55 (1H, dd, J=8.0, 1.2 Hz).

Production Example 971-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-[2-(methylthio)phenyl]ethanone

The title compound (244 mg, 80% yield) was obtained in the same manneras Production Example 96 from 250 mg of1-(piperidin-4-yl)-2-[2-(methylthio)phenyl]ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45 (9H, s), 1.55-1.66 (2H, m),1.82-1.91 (2H, m), 2.43 (3H, s), 2.59-2.68 (1H, m), 2.72-2.82 (2H, m),3.89 (2H, s), 4.02-4.16 (2H, m), 7.08-7.16 (2H, m), 7.24-7.29 (2H, m).

Production Example 98 5-tert-Butoxy-3-chloropyrazine-2-carboxaldehyde

The title compound (146 mg, 10% yield) was obtained in the same manneras Production Example 1 from 1.20 g of 2-tert-butoxy-6-chloropyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.66 (9H, s), 8.14 (1H, s), 10.22 (1H,s).

Production Example 99 6-tert-Butoxypyrazine-2-carboxaldehyde

After adding 7.20 g of AD-mix-β to 60 ml of 50% aqueous tert-butanol, asolution of 1.00 g of 2-tert-butoxy-6-vinylpyrazine in tert-butanol (5ml) was added and the mixture was stirred overnight at room temperature.Next, 8.40 g of sodium sulfite was added to the reaction solution, themixture was stirred at room temperature for 1 hour, and then water wasadded and extraction was performed with ethyl acetate. The organic layerwas washed with water and saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was dissolved in 40 ml of methanol, an aqueoussolution of 2.35 g of sodium periodate (20 ml) was added while stirringon ice, and stirring was continued at room temperature for 40 minutes.Water was added to the reaction solution, and extraction was performedwith ethyl acetate. The extract was washed with water and saturatedbrine and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (954 mg, 96% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.66 (9H, s), 8.27 (1H, s), 8.63 (1H,s), 9.99 (1H, s).

Production Example 100 3-Methoxy-5-methylpyrazine-2-carboxaldehyde

After dissolving 3.34 g of 5-chloro-3-methoxypyrazine-2-carboxaldehydedimethylacetal in 50 ml of tetrahydrofuran, 400 mg of[1,3-bis(diphenylphosphino)propane]dichloronickel (II) was added, 9.17ml of dimethyl zinc (2.0 M, toluene solution) was added dropwise under anitrogen atmosphere, and the mixture was stirred at room temperature for2 hours and then at 50° C. for 1.5 hours. The reaction solution wascooled on ice, water was added and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine inthat order and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue wasdissolved in 16 ml of acetone, 4 ml of 5N hydrochloric acid was addedand the mixture was allowed to stand at room temperature for 15 minutes.A sodium bicarbonate solution was added to the reaction solution andextraction was performed with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (1.43 g, 61%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.57 (3H, s), 4.10 (3H, s), 8.21 (1H,s), 10.22 (1H, s).

Production Example 101 5-Chloro-3-methoxypyrazine-2-carboxaldehyde

After dissolving 11.4 ml of 2,2,6,6-tetramethylpiperidine in 100 ml oftetrahydrofuran, the solution was cooled to −30° C. Next, 24.1 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise under anitrogen atmosphere. After stirring for 15 minutes and cooling on ice,the mixture was stirred for 10 minutes. It was then cooled to −78° C.,and a solution of 6.96 g of 2-chloro-6-methoxypyrazine intetrahydrofuran (10 ml) was added dropwise at below −70° C. The mixturewas stirred for 30 minutes, and then 6 ml of N,N-dimethylformamide wasadded dropwise at below −65° C. After 10 minutes, 50 ml of toluene wasadded to the reaction solution at below −60° C., and then after 2minutes, a tetrahydrofuran solution (5 ml) containing 2 ml of water wasadded at below −65° C. After an additional 5 minutes, 60 ml of 50%aqueous acetic acid was added at once, and then after 15 minutes, 100 mlof water was added and the temperature was raised to room temperature.The reaction solution was extracted with ethyl acetate, and the organiclayer was washed with water, a 1N sodium hydroxide solution andsaturated brine in that order and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure and theresidue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (6.38 g, 77%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 4.14 (3H, s), 8.33 (1H, s), 10.20 (1H,s).

Production Example 102 4-Bromothiophene-3-carboxaldehyde

After dissolving 25.2 g of 3,4-dibromothiophene in 300 ml of diethylether, the solution was cooled to −78° C. Next, 44.1 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise whilestirring at below −60° C. After 1 hour, 9.66 ml of N,N-dimethylformamidewas added dropwise at below −60° C. After an additional 45 minutes,water was added to the reaction solution, the temperature was returnedto room temperature, and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (14.78 g, 74% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 7.36 (1H, d, J=3.6 Hz), 8.15 (1H, dJ=3.6 Hz), 9.34 (1H, s).

Production Example 103 3-Methoxy-6-methylpyrazine-2-carboxaldehyde

After dissolving 300 mg of methyl3-methoxy-6-methylpyrazine-2-carboxylate in a mixture of 5 ml toluene/5ml dichloromethane, the solution was cooled to −78° C. Next, 1.21 ml ofdiisobutylaluminium hydride (1.5 M, toluene solution) was added dropwiseand the mixture was stirred for 1 hour. After adding 10 ml of 1Nhydrochloric acid dropwise to the reaction solution, extraction wasperformed with ethyl acetate. The organic layer was washed with 1Nhydrochloric acid, a saturated sodium bicarbonate solution and saturatedbrine in that order and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (118 mg, 47% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.58 (3H, s), 4.09 (3H, s), 8.20 (1H,s), 10.24 (1H, s).

Production Example 104 6-Fluoro-3-methoxypyrazine-2-carboxaldehyde

After dissolving 447 mg of methyl6-fluoro-3-methoxypyrazine-2-carboxylate in 8 ml of dichloromethane, thesolution was cooled to −78° C. Next, 1.76 ml of diisobutylaluminiumhydride (1.5 M, toluene solution) was added dropwise and the mixture wasstirred for 30 minutes. After adding 10 ml of 1N hydrochloric aciddropwise to the reaction solution, water was added and extraction wasperformed with dichloromethane. After then drying over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (245 mg, 65%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 4.13 (3H, s), 8.23 (1H, d, J=8.0 Hz),10.16 (1H, s).

Production Example 105 3-tert-Butoxy-5-fluoropyrazine-2-carboxaldehyde

After dissolving 11.4 ml of 2,2,6,6-tetramethylpiperidine in 100 ml oftetrahydrofuran, the solution was cooled to −30° C. Next, 24.1 ml ofn-butyllithium (2.6 M, n-hexane solution) was added dropwise under anitrogen atmosphere. After stirring for 5 minutes, the mixture wascooled on ice and stirred for an additional 20 minutes. It was thencooled to −78° C., and a solution of 9.00 g of2-tert-butoxy-6-chloropyrazine in tetrahydrofuran (10 ml) was addeddropwise at below −70° C. The mixture was then stirred for 30 minutes,and 6 ml of N,N-dimethylformamide was added dropwise at below −65° C.After 10 minutes, 50 ml of toluene was added to the reaction solution atbelow −60° C., and after 2 minutes, a tetrahydrofuran solution (5 ml)containing 2 ml of water was added at below −65° C. After an additional5 minutes, 60 ml of 50% aqueous acetic acid was added at once, and after5 minutes, 100 ml of water was added and the temperature was raised toroom temperature. The reaction solution was extracted with ethylacetate, washed with water, a 1N sodium hydroxide solution, water andsaturated brine in that order, and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to obtain9.39 g of crude 3-tert-butoxy-5-chloropyrazine-2-carboxaldehyde.

After dissolving 5.86 g of the crude3-tert-butoxy-5-chloropyrazine-2-carboxaldehyde in 55 ml ofacetonitrile, 4.77 g of potassium fluoride, 1.13 g oftetraphenylphosphonium bromide and 0.71 g of 18-crown-6 were added andthe mixture was heated to reflux for 4 hours. Diethyl ether was added tothe reaction mixture, the insoluble portion was filtered out, and thefiltrate was distilled off under reduced pressure. Ethyl acetate wasadded to the residue, the insoluble portion was filtered out, and thefiltrate was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: toluene/ethylacetate) to obtain the title compound (183 mg, 3% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.64 (9H, s), 8.08 (1H, d, J=8.4 Hz),10.22 (1H, s).

Production Example 1061-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-fluoro-3-thienyl)ethanol

After dissolving 304 mg of 2-(2-fluoro-3-thienyl)-1-(4-pyridyl)ethanonein 2 ml of toluene, 0.20 ml of benzyl bromide was added, the mixture wasstirred at 100° C. for 8 hours and the precipitate was filtered out. Thefiltered substance was dissolved in 10 ml of methanol, 157 mg of sodiumborohydride was added thereto in small portions at a time while coolingon ice, and the mixture was stirred for 1 hour. The reaction solutionwas distilled off under reduced pressure, water was added and extractionwas performed with ethyl acetate. The organic layer was washed withwater and saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by NH silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (384 mg, 88%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.13-2.29 (2H, m), 2.54-2.64 (2H, m),2.73 (1H, dd, J=14.4, 8.0 Hz), 2.80 (1H, dd, J=14.4, 4.4 Hz), 2.96-3.02(2H, m), 3.58 (2H, s), 4.18-4.24 (1H, m), 5.58-5.62 (1H, m), 6.68 (1H,dd, J=6.0, 3.6 Hz), 6.67 (1H, dd, J=6.0, 4.0 Hz), 7.22-7.38 (5H, m).

Production Example 1071-[1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (165 mg, 7% yield) was obtained in the same manner asProduction Example 26 from 1.96 g ofN-methoxy-N-methyl-1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxamide[CAS No. 189442-91-9] and 3.20 g of 2-fluorobenzyl chloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.27 (3H, s), 1.42-1.54 (2H, m), 1.45(9H, s), 2.04-2.12 (2H, m), 3.13-3.22 (2H, m), 3.54-3.67 (2H, m), 3.80(2H, s), 7.03 (1H, ddd, J=10.0, 8.4, 1.2 Hz), 7.09 (1H, dt, J=7.2, 1.2Hz), 7.15 (1H, dt, J=7.2, 1.2 Hz), 7.21-7.27 (1H, m).

Production Example 1081-[1-(tert-Butoxycarbonyl)-4-fluoropiperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (955 mg, 35% yield) was obtained in the same manneras Production Example 26 from 2.33 g ofN-methoxy-N-methyl-1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxamideand 4.51 g of 2-fluorobenzyl chloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.77-2.04 (4H, m),3.02-3.18 (2H, m), 3.90-4.18 (2H, m), 4.01 (2H, d, J=2.8 Hz), 7.01-7.17(3H, m), 7.23-7.29 (1H, m).

Production Example 1091-(tert-Butoxycarbonyl)-4-[3-(2-fluorophenyl)-2-oxopropyl]piperidine

The title compound (1.86 g, 78% yield) was obtained in the same manneras Production Example 26 from 2.04 g ofN-methoxy-N-methyl-1-(tert-butoxycarbonyl)-piperidine-4-acetamide and2.06 g of 2-fluorobenzyl chloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.00-1.13 (2H, m), 1.44 (9H, s),1.57-1.66 (2H, m), 1.94-2.06 (1H, m), 2.40 (2H, d, J=6.4 Hz), 2.62-2.78(2H, m), 3.70 (2H, s), 3.92-4.14 (2H, m), 7.02-7.18 (3H, m), 7.22-7.29(1H, m).

Production Example 1101-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-3-(2-fluorophenyl)propanone

The title compound (0.79 g, 43% yield) was obtained in the same manneras Production Example 26 from 1.50 g ofN-methoxy-N-methyl-1-(tert-butoxycarbonyl)-piperidine-4-carboxamide and1.46 g of 2-(2-fluorophenyl)ethyl bromide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44 (9H, s), 1.45-1.55 (2H, m),1.72-1.82 (2H, m), 2.43 (1H, dt, J=7.6, 3.6 Hz), 2.68-2.81 (4H, m), 2.91(2H, t, J=7.6 Hz), 3.98-4.18 (2H, m), 6.96-7.06 (2H, m), 7.13-7.20 (2H,m).

Production Example 111trans-1-(1-Benzyl-3-methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone

trans-1-(1-Benzyl-3-methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanol wasobtained in the same manner as Production Example 11 from 1.20 g oftrans-1-benzyl-3-methylpiperidine-4-carboxaldehyde and 2.64 g of2-fluorobenzyl chloride, and was subjected to the same process as inProduction Example 15 to obtain the title compound (0.69 g, 39% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.77 (3H, d, J=6.4 Hz), 1.59-1.82 (3H,m), 1.92 (1H, dt, J=10.2, 3.2 Hz), 2.00-2.12 (1H, m), 2.16-2.22 (1H, m),2.84 (1H, ddd, J=11.2, 3.6, 1.6 Hz), 2.91-2.96 (1H, m), 3.48 (2H, s),3.73 (1H, dd, J=16.4, 1.2 Hz), 3.78 (1H, dd, J=16.4, 1.2 Hz), 7.01-7.10(2H, m), 7.14 (1H, dt, J=7.6, 1.6 Hz), 7.20-7.33 (6H, m).

Production Example 1121-(tert-Butoxycarbonyl)-4-[(2-fluorophenylthio)methyl]piperidine

After dissolving 1.97 g of 2-fluorothiophenol in 50 ml oftetrahydrofuran, 3.0 g of 1-(tert-butoxycarbonyl)piperidine-4-methanoland 4.03 g of triphenylphosphine were added, and then 3.3 ml of diethylazodicarboxylate was added dropwise while cooling on ice and the mixturewas stirred overnight at room temperature. The reaction solution wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate) to obtainthe title compound (216 mg, 5% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.11-1.23 (2H, m), 1.45 (9H, s),1.55-1.70 (1H, m), 1.81-1.89 (2H, m), 2.60-2.74 (2H, m), 2.82 (2H, d,J=6.4 Hz), 4.03-4.16 (2H, m), 7.04 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.08(1H, td, J=7.6, 1.6 Hz), 7.17-7.24 (1H, m), 7.35 (1H, td, J=7.6, 1.6Hz).

Production Example 113 4-(2-Fluorobenzylsulfonyl)piperidinehydrochloride

After dissolving 690 mg of1-(tert-butoxycarbonyl)-4-(2-fluorobenzylsulfonyl)piperidine in 3 ml ofethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added andthe mixture was stirred at room temperature for 30 minutes. Theprecipitate was filtered out to obtain the title compound (517 mg, 91%yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.82-1.95 (2H, m), 2.20-2.29 (2H, m),2.90-3.00 (2H, m), 3.37-3.53 (3H, m), 4.57 (2H, s), 7.22-7.31 (2H, m),7.42-7.49 (2H, m).

Production Example 114 4-[(2-Fluorophenylthio)methyl]piperidinehydrochloride

The title compound (52 mg, 85% yield) was obtained in the same manner asProduction Example 113 from 76 mg of1-(tert-butoxycarbonyl)-4-[(2-fluorophenylthio)methyl]piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.33-1.45 (2H, m), 1.69-1.81 (1H, m),1.91-1.98 (2H, m), 2.78-2.87 (2H, m), 2.95 (2H, d, J=6.4 Hz), 3.20-3.27(2H, m), 7.17-7.31 (3H, m), 7.47 (1H, td, J=7.6, 1.6 Hz), 8.50 (2H, brs).

Production Example 115 4-[(2-Fluorophenylsulfonyl)methyl]piperidinehydrochloride

The title compound (36 mg, 85% yield) was obtained in the same manner asProduction Example 113 from 52 mg of1-(tert-butoxycarbonyl)-4-[(2-fluorophenylsulfonyl)methyl]piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.42-1.55 (2H, m), 1.90-1.98 (2H, m),2.14-2.26 (1H, m), 2.84-2.93 (2H, m), 3.17-3.24 (2H, m), 3.46 (2H, d,J=6.4 Hz), 7.49 (1H, td, J=7.6, 1.2 Hz), 7.54 (1H, ddd, J=10.6, 8.4, 1.2Hz), 7.80-7.90 (2H, m).

Production Example 116 2-(2-Fluorophenyl)-1-(piperidin-4-yl)propanone

After dissolving 1.16 g of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-fluorophenyl)propanone in10 ml of ethyl acetate, 10 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was stirred at room temperature for 1 hour. A 5Nsodium hydroxide solution was added to the reaction solution, andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain the title compound (763 mg, 94% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.37 (3H, d, J=6.8 Hz), 1.40-1.60 (3H,m), 1.79-1.86 (1H, m), 2.44-2.62 (3H, m), 2.99-3.12 (2H, m), 4.27 (1H,q, J=6.8 Hz), 7.05 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.11 (1H, dd, J=7.6,1.2 Hz), 7.16 (1H, td, J=7.6, 2.0 Hz), 7.20-7.26 (1H, m).

Production Example 117 4-(2-Chlorophenoxymethyl)-4-methylpiperidine

After dissolving 810 mg of1-(tert-butoxycarbonyl)-4-(2-chlorophenoxymethyl)-4-methylpiperidine in3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was allowed to stand at room temperature for 2.5hours. A sodium carbonate solution was added to the reaction solution,and extraction was performed with dichloromethane. After drying overanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure to obtain the title compound (521 mg, 91% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.16 (3H, s), 1.44-1.51 (2H, m),1.61-1.69 (2H, m), 2.82-2.94 (4H, m), 3.72 (2H, s), 6.83-6.91 (2H, m),7.18 (1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.34 (1H, dd, J=8.0, 1.6 Hz).

Production Example 118 4-Methyl-4-(2-methylphenoxymethyl)piperidine

The title compound (536 mg, 96% yield) was obtained in the same manneras Production Example 117 from 816 mg of1-(tert-butoxycarbonyl)-4-methyl-4-(2-methylphenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.13 (3H, s), 1.42-1.50 (2H, m),1.59-1.69 (2H, m), 2.24 (3H, s), 2.82-2.94 (4H, m), 3.67 (2H, s),6.76-6.86 (2H, m), 7.10-7.17 (2H, m).

Production Example 119 4-(2-Methoxyphenoxymethyl)-4-methylpiperidine

The title compound (190 mg, 93% yield) was obtained in the same manneras Production Example 117 from 293 mg of1-(tert-butoxycarbonyl)-4-(2-methoxyphenoxymethyl)-4-methylpiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.14 (3H, s), 1.43-1.51 (2H, m),1.63-1.72 (2H, m), 2.83-2.98 (4H, m), 3.71 (2H, s), 3.84 (3H, s),6.85-6.93 (4H, m).

Production Example 1202-[2-(Methylsulfonyl)phenyl]-1-(piperidin-4-yl)ethanone hydrochloride

The title compound (169 mg, 94% yield) was obtained in the same manneras Production Example 113 from 217 mg of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-[2-(methylsulfonyl)phenyl]ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.64-1.75 (2H, m), 2.02-2.09 (2H, m),2.82-2.98 (3H, m), 3.14 (3H, s), 3.25-3.34 (2H, m), 4.33 (2H, s), 7.37(1H, dd, J=7.8, 1.4 Hz), 7.54 (1H, td, J=7.8, 1.4 Hz), 7.66 (1H, td,J=7.8, 1.4 Hz), 7.92 (1H, dd, J=7.8, 1.4 Hz), 8.55 (2H, br s).

Production Example 121 2-(2-Fluoro-3-thienyl)-1-(4-pyridyl)ethanone

The title compound (304 mg, 63% yield) was obtained in the same manneras Production Example 61 from 912 mg of[(phenylamino)-(4-pyridylmethyl)]phosphonic acid diphenyl ester and 285mg of 2-fluorothiophene-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 4.19 (2H, d, J=0.8 Hz), 6.64-6.69 (2H,m), 7.75-7.80 (2H, m), 8.81-8.86 (2H, m).

Production Example 1222-(Piperidin-4-yl)-3-(2-fluorophenyl)propionitrile hydrochloride

The title compound (746 mg, 76% yield) was obtained in the same manneras Production Example 113 from 1.21 g of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrile.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.50-1.64 (2H, m), 1.86-1.98 (2H, m),1.98-2.06 (1H, m), 2.80-2.97 (4H, m), 3.13-3.20 (1H, m), 3.24-3.38 (2H,m), 7.16-7.24 (2H, m), 7.30-7.37 (1H, m), 7.42 (1H, td, J=7.6, 1.6 Hz),8.47-8.62 (1H, m), 8.97-9.08 (1H, m).

Production Example 1232-(Piperidin-4-yl)-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrilehydrochloride

The title compound (669 mg, 77% yield) was obtained in the same manneras Production Example 113 from 1.02 g of2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrile.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.74-1.88 (3H, m), 1.99-2.07 (2H, m),2.80-2.93 (4H, m), 3.10 (2H, d, J=14.0 Hz), 3.31-3.42 (2H, m), 7.16-7.25(4H, m), 7.32-7.40 (4H, m), 8.62-8.78 (1H, m), 8.82-8.96 (1H, m).

Production Example 1242-(2-Fluorophenyl)-1-(4-methylpiperidin-4-yl)ethanone hydrochloride

The title compound (126 mg, 95% yield) was obtained in the same manneras Production Example 113 from 165 mg of1-[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35 (3H, s), 1.92-2.02 (2H, m),2.31-2.39 (2H, m), 2.90-3.02 (2H, m), 3.28-3.37 (2H, m), 3.79 (2H, s),7.01-7.07 (1H, m), 7.09-7.19 (2H, m), 7.24-7.30 (1H, m), 9.40-9.66 (2H,m).

Production Example 1252-(2-Fluorophenyl)-1-(4-fluoropiperidin-4-yl)ethanone hydrochloride

The title compound (724 mg, 94% yield) was obtained in the same manneras Production Example 113 from 955 mg of1-[1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 2.02-2.26 (4H, m), 2.98-3.10 (2H, m),3.28-3.36 (2H, m), 4.15 (2H, d, J=2.0 Hz), 7.13-7.20 (2H, m), 7.26-7.36(2H, m), 8.98-9.30 (2H, m).

Production Example 1261-(4-Fluoropiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanonehydrochloride

The title compound (667 mg, 98% yield) was obtained in the same manneras Production Example 113 from 0.82 g of1-[1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 2.02-2.22 (4H, m), 3.06 (2H, dt,J=12.4, 4.4 Hz), 3.28-3.37 (2H, m), 4.33 (2H, s), 7.44 (1H, d, J=7.6Hz), 7.50 (1H, t, J=7.6 Hz), 7.65 (1H, t, J=7.6 Hz), 7.71 (1H, d, J=7.6Hz), 9.00 (2H, br s).

Production Example 1271-(4-Methylpiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanonehydrochloride

The title compound (45 mg, 100% yield) was obtained in the same manneras Production Example 113 from 54 mg of1-[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.28 (3H, s), 1.66-1.75 (2H, m),2.09-2.17 (2H, m), 2.86-2.96 (2H, m), 3.10-3.20 (2H, m), 4.18 (2H, s),7.38 (1H, d, J=7.6 Hz), 7.47 (1H, t, J=7.6 Hz), 7.62 (1H, t, J=7.6 Hz),7.69 (1H, d, J=7.6 Hz), 8.64-8.90 (2H, m).

Production Example 128 4-[3-(2-Fluorophenyl)-2-oxopropyl]piperidinehydrochloride

The title compound (1.27 g, 84% yield) was obtained in the same manneras Production Example 113 from 1.86 g of1-(tert-butoxycarbonyl)-4-[3-(2-fluorophenyl)-2-oxopropyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54-1.66 (2H, m), 1.83-1.91 (2H, m),2.04-2.17 (1H, m), 2.49 (2H, d, J=6.8 Hz), 2.78-2.91 (2H, m), 3.38-3.46(2H, m), 3.69 (2H, s), 7.12-7.18 (3H, m), 7.24-7.30 (1H, m), 9.20-9.38(1H, m), 9.52-9.67 (1H, m).

Production Example 129 1-(Piperidin-4-yl)-3-(2-fluorophenyl)propanonehydrochloride

The title compound (0.52 g, 80% yield) was obtained in the same manneras Production Example 113 from 0.79 g of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-(2-fluorophenyl)propanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.94-2.04 (2H, m), 2.06-2.15 (2H, m),2.51-2.59 (1H, m), 2.78 (2H, t, J=7.2 Hz), 2.89-3.02 (4H, m), 3.34-3.43(2H, m), 6.96-7.06 (2H, m), 7.13-7.21 (2H, m), 9.42 (1H, br s), 9.62(1H, br s).

Production Example 1301-(Piperidin-4-yl)-2-[2-(3-pyridyl)phenyl]ethanone

The title compound (239 mg, 85% yield) was obtained in the same manneras Production Example 117 from 379 mg of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-[2-(3-pyridyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.48 (2H, m), 1.58-1.66 (2H, m),2.29-2.38 (1H, m), 2.48-2.60 (2H, m), 3.03-3.10 (2H, m), 3.72 (2H, s),7.16-7.42 (5H, m), 7.54-7.58 (1H, m), 8.49 (1H, d, J=1.2 Hz), 8.56-8.62(1H, m).

Production Example 131 4-[2-(Methoxycarbonyl)phenoxymethyl]piperidinehydrochloride

The title compound (190 mg, 100% yield) was obtained in the same manneras Production Example 113 from 226 mg of1-(tert-butoxycarbonyl)-4-[2-(methoxycarbonyl)phenoxymethyl]piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.44-1.57 (2H, m), 1.90-1.98 (2H, m),2.01-2.22 (1H, m), 2.84-2.97 (2H, m), 3.27-3.35 (2H, m), 3.80 (3H, s),3.93 (2H, d, J=6.0 Hz), 7.02 (1H, t, J=7.6 Hz), 7.15 (1H, d, J=8.0 Hz),7.50-7.56 (1H, m), 7.66 (1H, dd, J=7.6, 1.6 Hz), 8.52-8.66 (1H, m),8.86-9.02 (1H, m).

Production Example 132 4-(2-Acetylphenoxymethyl)piperidine hydrochloride

The title compound (177 mg, 100% yield) was obtained in the same manneras Production Example 113 from 220 mg of1-(tert-butoxycarbonyl)-4-(2-acetylphenoxymethyl)piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.51-1.63 (2H, m), 1.89-1.97 (2H, m),2.07-2.19 (1H, m), 2.56 (3H, s), 2.85-2.97 (2H, m), 3.26-3.34 (2H, m),4.00 (2H, d, J=6.0 Hz), 7.02 (1H, dt, J=7.6, 0.8 Hz), 7.17 (1H, d, J=8.0Hz), 7.50-7.55 (1H, m), 7.57 (1H, dd, J=7.6, 2.0 Hz), 8.50-8.85 (1H, m),8.94-9.08 (1H, m).

Production Example 133 4-(2-Carbamoylphenoxymethyl)piperidine

The title compound (105 mg, 91% yield) was obtained in the same manneras Production Example 117 from 165 mg of1-(tert-butoxycarbonyl)-4-(2-carbamoylphenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.28-1.40 (2H, m), 1.76-1.86 (2H, m),1.95-2.07 (1H, m), 2.62-2.73 (2H, m), 3.11-3.19 (2H, m), 3.98 (2H, d,J=6.4 Hz), 5.97 (1H, br s), 6.98 (1H, d, J=8.8 Hz), 7.03-7.12 (1H, m),7.42-7.49 (1H, m), 7.76 (1H, br s), 8.20 (1H, dd, J=8.0, 1.6 Hz).

Production Example 134 4-(2-Nitrophenoxymethyl)piperidine hydrochloride

The title compound (132 mg, 85% yield) was obtained in the same manneras Production Example 113 from 191 mg of1-(tert-butoxycarbonyl)-4-(2-nitrophenoxymethyl)piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.44-1.57 (2H, m), 1.86-1.94 (2H, m),2.02-2.15 (1H, m), 2.84-2.96 (2H, m), 3.26-3.34 (2H, m), 4.06 (2H, d,J=6.4 Hz), 7.09-7.15 (1H, m), 7.37 (1H, d, J=7.6 Hz), 7.63-7.69 (1H, m),7.87 (1H, dd, J=8.0, 1.6 Hz), 8.51-8.66 (1H, m), 8.89-9.04 (1H, m).

Production Example 135 4-[2-(Acetylamino)phenoxymethyl]piperidinehydrochloride

The title compound (379 mg, 100% yield) was obtained in the same manneras Production Example 113 from 459 mg of1-(tert-butoxycarbonyl)-4-[2-(acetylamino)phenoxymethyl]piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.52-1.64 (2H, m), 1.91-1.99 (2H, m),2.03-2.16 (4H, m), 2.82-2.94 (2H, m), 3.25-3.34 (2H, m), 3.90 (2H, d,J=6.4 Hz), 6.85-6.92 (1H, m), 6.99-7.10 (2H, m), 7.83 (1H, d, J=7.6 Hz),8.80-9.02 (3H, m).

Production Example 1364-[2-(Methanesulfonylamino)phenoxymethyl]piperidine

The title compound (271 mg, 80% yield) was obtained in the same manneras Production Example 117 from 447 mg of1-(tert-butoxycarbonyl)-4-[2-(methanesulfonylamino)phenoxymethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.23-1.34 (2H, m), 1.77-1.84 (2H, m),1.90-2.03 (1H, m), 2.63-2.71 (2H, m), 2.96 (3H, s), 3.10-3.16 (2H, m),3.86 (2H, d, J=6.4 Hz), 6.90 (1H, dd, J=8.0, 1.2 Hz), 6.97 (1H, dt,J=8.0, 1.2 Hz), 7.09-7.15 (1H, m), 7.65 (1H, dd, J=7.6, 1.2 Hz).

Production Example 137 4-[2-(Dimethylamino)phenoxymethyl]piperidine

The title compound (277 mg, 91% yield) was obtained in the same manneras Production Example 117 from 447 mg of1-(tert-butoxycarbonyl)-4-[2-(dimethylamino)phenoxymethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.33-1.46 (2H, m), 1.85-2.15 (3H, m),2.67-2.75 (2H, m), 2.80 (6H, s), 3.18-3.24 (2H, m), 3.85 (2H, d, J=6.8Hz), 6.82-6.96 (4H, m).

Production Example 138 4-[2-(3-Methylthioureido)phenoxymethyl]piperidinehydrochloride

The title compound (430 mg, 100% yield) was obtained in the same manneras Production Example 113 from 537 mg of1-(tert-butoxycarbonyl)-4-[2-(3-methylthioureido)phenoxymethyl]piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.55-1.68 (2H, m), 1.88-1.96 (2H, m),2.01-2.13 (1H, m), 2.83-2.95 (5H, m), 3.26-3.34 (2H, m), 3.88 (2H, d,J=6.0 Hz), 6.88-6.94 (1H, m), 7.02-7.06 (1H, m), 7.09-7.16 (1H, m),7.68-7.78 (1H, m), 8.21 (1H, br s), 8.68-8.95 (3H, m).

Production Example 139 4-[2-(3-Methylureido)phenoxymethyl]piperidine

The title compound (320 mg, 94% yield) was obtained in the same manneras Production Example 117 from 469 mg of1-(tert-butoxycarbonyl)-4-[2-(3-methylureido)phenoxymethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.57 (2H, m), 1.72-1.79 (2H, m),1.87-1.99 (1H, m), 2.61-2.70 (2H, m), 2.84 (3H, d, J=4.4 Hz), 3.11-3.20(2H, m), 3.86 (2H, d, J=5.6 Hz), 5.33 (1H, br s), 6.68-6.99 (4H, m),8.01 (1H, dd, J=7.2, 2.0 Hz).

Production Example 140 cis-3-(2-Fluorophenoxymethyl)-4-hydroxypiperidine

After dissolving 402 mg ofcis-1-benzyl-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine in 20 ml ofethanol, 0.2 g of 20% palladium hydroxide-carbon (hydrous) was added andthe mixture was stirred at room temperature under a hydrogen atmosphere(1 atm). The mixture was further stirred for 5.5 hours, and then ethylacetate was added thereto and the insoluble portion was filtered off.The filtrate was distilled off under reduced pressure to obtain thetitle compound (276 mg, 94% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.70-1.79 (2H, m), 2.15-2.24 (1H, m),2.80 (1H, dt, J=8.8, 4.4 Hz), 2.87 (1H, dd, J=12.0, 4.4 Hz), 2.94-3.10(2H, m), 4.07 (1H, dd, J=9.6, 6.4 Hz), 4.16 (1H, dd, J=9.2, 6.4 Hz),4.20-4.25 (1H, m), 6.85-6.92 (1H, m), 6.95-7.09 (3H, m).

Production Example 141trans-3-(2-Fluorophenoxymethyl)-4-hydroxypiperidine

The title compound (203 mg, 90% yield) was obtained in the same manneras Production Example 140 from 326 mg oftrans-1-benzyl-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.54 (1H, m), 1.89-2.10 (2H, m),2.49 (1H, dd, J=12.8, 11.2 Hz), 2.64 (1H, dd, J=12.8, 2.8 Hz), 2.99-3.16(1H, m), 3.22 (1H, ddd, J=12.8, 4.4, 1.6 Hz), 3.69 (1H, dt, J=10.4, 4.4Hz), 4.12 (2H, d, J=6.0 Hz), 6.86-6.93 (1H, m), 6.98 (1H, dt, J=8.4, 1.6Hz), 7.01-7.09 (2H, m).

Production Example 1421-(1-Benzylpiperidin-4-yl)-2-(3-methyl-2-thienyl)ethanone

The title compound (858 mg, 76% yield) was obtained in the same manneras Production Example 140 from 1.12 g of1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-methyl-2-thienyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.67-1.83 (4H, m), 1.95-2.03 (2H, m),2.12 (3H, s), 2.41-2.49 (1H, m), 2.87-2.93 (2H, m), 3.48 (2H, s), 3.81(2H, s), 6.80 (1H, d, J=5.2 Hz), 7.09 (1H, d, J=5.2 Hz), 7.20-7.33 (5H,m).

Production Example 1431-(tert-Butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine

The title compound (4.28 g, 88% yield) was obtained in the same manneras Production Example 140 from 5.34 g of1-(tert-butoxycarbonyl)-4-(2-nitrophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.36 (2H, m), 1.47 (9H, s),1.79-1.86 (2H, m), 1.94-2.06 (1H, m), 2.68-2.84 (2H, m), 3.77 (2H, brs), 3.85 (2H, d, J=6.0 Hz), 4.06-4.26 (2H, m), 6.68-6.82 (4H, m).

Production Example 1441-(1-Benzylpiperidin-4-yl)-2-(4-fluoro-3-thienyl)ethanone

The title compound (1.26 g, 78% yield) was obtained in the same manneras Production Example 140 from 1.61 g of1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-3-thienyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.67-1.78 (2H, m), 1.80-1.87 (2H, m),1.97-2.05 (2H, m), 2.38-2.47 (1H, m), 2.88-2.95 (2H, m), 3.50 (2H, s),3.76 (2H, s), 6.70 (1H, d, J=3.6 Hz), 7.01-7.05 (1H, m), 7.22-7.35 (5H,m).

Production Example 1451-(1-Benzylpiperidin-4-yl)-2-(2,3-dihydrobenzofuran-7-yl)ethanone

The title compound (159 mg, 15% yield) was obtained in the same manneras Production Example 16 from 935 mg of2,3-dihydrobenzofuran-7-carboxaldehyde and 641 mg of1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.66-1.78 (2H, m), 1.78-1.87 (2H, m),1.95-2.03 (2H, m), 2.40-2.48 (1H, m), 2.87-2.93 (2H, m), 3.21 (2H, t,J=8.8 Hz), 3.49 (2H, s), 3.68 (2H, s), 4.53 (2H, t, J=8.8 Hz), 6.79 (1H,t, J=7.4 Hz), 6.91 (1H, d, J=7.4 Hz), 7.09 (1H, dd, J=7.4, 1.2 Hz),7.21-7.36 (5H, m).

Production Example 1461-(1-Benzylpiperidin-4-yl)-2-[2-(methylthio)phenyl]ethanone

The title compound (768 mg, 29% yield) was obtained in the same manneras Production Example 16 from 2.40 g of 2-(methylthio)benzaldehyde and1.60 g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.71-1.82 (2H, m), 1.82-1.91 (2H, m),1.97-2.05 (2H, m), 2.42 (3H, s), 2.42-2.53 (1H, m), 2.88-2.96 (2H, m),3.50 (2H, s), 3.89 (2H, s), 7.08-7.17 (2H, m), 7.22-7.36 (7H, m).

Production Example 1471-(1-Benzylpiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone

After dissolving 2.57 g of 2-(trifluoromethyl)benzaldehyde in 15 ml ofmethanol, 2.75 g of p-toluenesulfonyl hydrazide was added, the mixturewas stirred at room temperature for 2 hours, and then 1.09 g ofpotassium methoxide and a methanol solution (4 ml) of 1.50 g of1-benzylpiperidine-4-carboxaldehyde was added, and the mixture wasshielded from light and stirred overnight at 55° C. The reactionsolution was concentrated under reduced pressure, water was added, andextraction was performed with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent:toluene/ethyl acetate) to obtain the title compound (1.30 g, 49% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.69-1.81 (2H, m), 1.82-1.90 (2H, m),1.98-2.06 (2H, m), 2.41-2.49 (1H, m), 2.89-2.96 (2H, m), 3.50 (2H, s),3.95 (2H, d, J=0.8 Hz), 7.14-7.38 (7H, m), 7.49 (1H, t, J=7.6 Hz), 7.63(1H, d, J=7.6 Hz).

Production Example 1481-(1-Benzylpiperidin-4-yl)-2-[2-(trifluoromethoxy)phenyl]ethanone

The title compound (1.12 g, 40% yield) was obtained in the same manneras Production Example 16 from 2.81 g of 2-(trifluoromethoxy)benzaldehydeand 1.50 g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.69-1.81 (2H, m), 1.81-1.90 (2H, m),1.97-2.06 (2H, m), 2.39-2.48 (1H, m), 2.89-2.96 (2H, m), 3.50 (2H, s),3.80 (2H, s), 7.15-7.33 (9H, m).

Production Example 1491-(1-Benzylpiperidin-4-yl)-2-(2-ethoxyphenyl)ethanone

The title compound (581 mg, 23% yield) was obtained in the same manneras Production Example 16 from 3.33 g of 2-ethoxybenzaldehyde and 1.50 gof 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35 (3H, t, J=7.0 Hz), 1.67-1.86 (4H,m), 1.94-2.02 (2H, m), 2.40-2.48 (1H, m), 2.86-2.92 (2H, m), 3.48 (2H,s), 3.70 (2H, s), 3.99 (2H, q, J=7.0 Hz), 6.82 (1H, d, J=7.6 Hz), 6.88(1H, td, J=7.6, 1.2 Hz), 7.08 (1H, dd, J=7.6, 2.0 Hz), 7.17-7.34 (6H,m).

Production Example 1501-(1-Benzylpiperidin-4-yl)-2-(2-n-propoxyphenyl)ethanone

The title compound (799 mg, 31% yield) was obtained in the same manneras Production Example 16 from 3.64 g of 2-n-propoxybenzaldehyde and 1.50g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.00 (3H, t, J=7.4 Hz), 1.67-1.85 (6H,m), 1.93-2.02 (2H, m), 2.48-2.57 (1H, m), 2.86-2.93 (2H, m), 3.48 (2H,s), 3.71 (2H, s), 3.88 (2H, t, J=6.6 Hz), 6.82 (1H, d, J=7.6 Hz), 6.87(1H, td, J=7.6, 0.8 Hz), 7.06-7.32 (7H, m).

Production Example 151 1-(1-Benzylpiperidin-4-yl)-2-(1-naphthyl)ethanone

The title compound (1.09 g, 43% yield) was obtained in the same manneras Production Example 16 from 2.31 g of 1-naphthylcarboxaldehyde and1.50 g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.80 (4H, m), 1.88-1.96 (2H, m),2.42-2.51 (1H, m), 2.84-2.90 (2H, m), 3.46 (2H, s), 4.16 (2H, s),7.14-7.34 (5H, m), 7.38-7.50 (4H, m), 7.75-7.86 (3H, m).

Production Example 152 1-(1-Benzylpiperidin-4-yl)-2-(2-biphenyl)ethanone

The title compound (1.45 g, 48% yield) was obtained in the same manneras Production Example 16 from 3.00 g of 2-biphenylcarboxaldehyde and1.67 g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.51-1.62 (4H, m), 1.84-1.92 (2H, m),2.10-2.19 (1H, m), 2.77-2.84 (2H, m), 3.44 (2H, s), 3.71 (2H, s),7.14-7.40 (14H, m).

Production Example 1531-(1-Benzylpiperidin-4-yl)-2-(2-bromophenyl)ethanone

The title compound (1.63 g, 44% yield) was obtained in the same manneras Production Example 16 from 3.65 g of 2-bromobenzaldehyde and 2.0 g of1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.83 (2H, m), 1.84-1.92 (2H, m),1.98-2.06 (2H, m), 2.43-2.52 (1H, m), 2.89-2.96 (2H, m), 3.50 (2H, s),3.90 (2H, s), 7.09-7.32 (8H, m), 7.54 (1H, dd, J=8.0, 1.2 Hz).

Production Example 154 1-(1-Benzylpiperidin-4-yl)-2-(3-pyridyl)ethanone

The title compound (925 mg, 43% yield) was obtained in the same manneras Production Example 16 from 1.59 g of 3-pyridinecarboxaldehyde and1.50 g of 1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.62-1.79 (2H, m), 1.80-1.88 (2H, m),1.96-2.06 (2H, m), 2.39-2.48 (1H, m), 2.88-2.95 (2H, m), 3.50 (2H, s),3.74 (2H, s), 7.21-7.33 (6H, m), 7.51 (1H, ddd, J=7.8, 2.4, 1.8 Hz),8.40 (1H, dd, J=2.4, 0.8 Hz), 8.49 (1H, dd, J=5.0, 1.8 Hz).

Production Example 1551-[1-(tert-Butoxycarbonyl)-4-fluoropiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone

The title compound (0.82 g, 27% yield) was obtained in the same manneras Production Example 16 from 2.68 g of 2-(trifluoromethyl)benzaldehydeand 1.73 g of1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.79-2.03 (4H, m),3.04-3.18 (2H, m), 3.96-4.15 (2H, m), 4.20 (2H, s), 7.20 (1H, d, J=7.6Hz), 7.36-7.42 (1H, m), 7.51 (1H, dt, J=7.6, 0.8 Hz), 7.64 (1H, d, J=7.6Hz).

Production Example 1561-[1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone

The title compound (54 mg, 2% yield) was obtained in the same manner asProduction Example 16 from 2.68 g of 2-(trifluoromethyl)benzaldehyde and1.74 g of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxaldehyde[CAS No. 189442-92-0].

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.28 (3H, s), 1.41-1.56 (2H, m), 1.46(9H, s), 2.01-2.09 (2H, m), 3.21-3.30 (2H, m), 3.51-3.63 (2H, m), 4.01(2H, s), 7.16 (1H, d, J=7.6 Hz), 7.37 (1H, t, J=7.6 Hz), 7.50 (1H, t,J=7.6 Hz), 7.65 (1H, d, J=7.6 Hz).

Production Example 1571-(1-Benzylpiperidin-4-yl)-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethanone

The title compound (136 mg, 3% yield) was obtained in the same manner asProduction Example 16 from 4.72 g of2-fluoro-6-(trifluoromethyl)benzaldehyde and 2.50 g of1-benzylpiperidine-4-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.84 (2H, m), 1.85-1.94 (2H, m),2.00-2.09 (2H, m), 2.44-2.52 (1H, m), 2.91-2.97 (2H, m), 3.51 (2H, s),3.98 (2H, s), 7.21-7.44 (8H, m).

Production Example 1581-(tert-Butoxycarbonyl)-4-(2-fluorobenzylsulfonyl)piperidine

After dissolving 695 mg of1-(tert-butoxycarbonyl)-4-(2-fluorobenzylthio)piperidine in 7 ml ofchloroform, 1.13 g of 3-chloroperbenzoic acid was added while cooling onice, and the mixture was stirred for 30 minutes. Aqueous sodiumthiosulfate solution was added to the reaction solution, and extractionwas performed with chloroform. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (690 mg, 90% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45 (9H, s), 1.71-1.84 (2H, m),2.03-2.11 (2H, m), 2.63-2.78 (2H, m), 2.86-2.95 (1H, m), 4.18-4.33 (2H,m), 4.29 (2H, s), 7.12 (1H, ddd, J=9.6, 8.0, 1.2 Hz), 7.21 (1H, td,J=8.0, 1.2 Hz), 7.36-7.42 (1H, m), 7.52 (1H, td, J=8.0, 2.0 Hz).

Production Example 1591-(tert-Butoxycarbonyl)-4-[(2-fluorophenylsulfinyl)methyl]piperidine

After dissolving 79 mg of1-(tert-butoxycarbonyl)-4-[(2-fluorophenylthio)methyl]piperidine in 3 mlof chloroform, 42 mg of 3-chloroperbenzoic acid was added while coolingon ice, and the mixture was stirred for 30 minutes. Aqueous sodiumthiosulfate solution was added to the reaction solution, and extractionwas performed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (68 mg, 82% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.23-1.40 (2H, m), 1.45 (9H, s),1.65-1.73 (1H, m), 2.07-2.27 (2H, m), 2.70-2.88 (4H, m), 4.04-4.22 (2H,m), 7.11 (1H, ddd, J=9.6, 7.6, 1.0 Hz), 7.38 (1H, td, J=7.6, 1.0 Hz),7.45-7.52 (1H, m), 7.84 (1H, td, J=7.6, 2.0 Hz).

Production Example 1601-(tert-Butoxycarbonyl)-4-[(2-fluorophenylsulfonyl)methyl]piperidine

The title compound (52 mg, 78% yield) was obtained in the same manner asProduction Example 158 from 61 mg of1-(tert-butoxycarbonyl)-4-[(2-fluorophenylthio)methyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.22-1.35 (2H, m), 1.44 (9H, s),1.82-1.92 (2H, m), 2.17-2.28 (1H, m), 2.67-2.80 (2H, m), 3.23 (2H, d,J=6.4 Hz), 3.98-4.13 (2H, m), 7.21-7.28 (1H, m), 7.34 (1H, td, J=8.0,1.2 Hz), 7.62-7.69 (1H, m), 7.94 (1H, ddd, J=8.4, 8.0, 1.8 Hz).

Production Example 1611-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

The title compound (217 mg, 82% yield) was obtained in the same manneras Production Example 158 from 244 mg of1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-[2-(methylthio)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46 (9H, s), 1.55-1.67 (2H, m),1.89-1.98 (2H, m), 2.67-2.75 (1H, m), 2.75-2.87 (2H, m), 3.01 (3H, s),4.08-4.21 (2H, m), 4.34 (2H, br s), 7.18 (1H, dd, J=7.6, 1.2 Hz), 7.48(1H, td, J=7.6, 1.2 Hz), 7.57 (1H, td, J=7.6, 1.6 Hz), 8.01 (1H, dd,J=7.6, 1.6 Hz).

Production Example 162 4-(2-Fluorobenzylthio)piperidine hydrochloride

The title compound (227 mg, 69% yield) was obtained in the same manneras Production Example 113 from 406 mg of1-(tert-butoxycarbonyl)-4-(2-fluorobenzylthio)piperidine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.59-1.71 (2H, m), 2.02-2.10 (2H, m),2.85-2.96 (3H, m), 3.18-3.25 (2H, m), 3.83 (2H, s), 7.14-7.22 (2H, m),7.29-7.35 (1H, m), 7.43 (1H, td, J=7.8, 2.0 Hz).

Production Example 1631-Benzyl-4-[2-(2-fluorophenyl)ethyl]-3-methoxy-1,2,5,6-tetrahydropyridine

After dissolving 1.12 g of 4-[2-(2-fluorophenyl)ethyl]-3-methoxypyridinein 10 ml of acetonitrile, 0.63 ml of benzyl bromide was added, themixture was stirred for 2 hours at 50° C., and the solvent was distilledoff under reduced pressure. The residue was dissolved in 20 ml ofmethanol, and then 552 mg of sodium borohydride was added while coolingon ice and the mixture was stirred for 1 hour. Water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and filtered with NH silica gel. The solvent wasdistilled off under reduced pressure to obtain the title compound (1.26g, 80% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.10-2.16 (2H, m), 2.37 (2H, t, J=8.0Hz), 2.52 (2H, t, J=5.6 Hz), 2.71 (2H, t, J=8.0 Hz), 2.99 (2H, br s),3.36 (3H, s), 3.60 (2H, s), 6.98 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.03(1H, td, J=7.6, 1.2 Hz), 7.10-7.17 (1H, m), 7.19 (1H, td, J=7.6, 2.0Hz), 7.23-7.36 (5H, m).

Production Example 1641-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-methyl-2-thienyl)ethanol

After dissolving 2.72 g of 2-(3-methyl-2-thienyl)-1-(4-pyridyl)ethanonein 15 ml of toluene, 1.79 ml of benzyl bromide was added, the mixturewas stirred for 7 hours at 110° C. and the precipitate was filtered out.The filtered substance was dissolved in 60 ml of methanol, 1.42 g ofsodium borohydride was added in small portions at a time while coolingon ice, and the mixture was stirred for 1 hour. The reaction solutionwas distilled off under reduced pressure, water was added, andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (2.85 g, 73%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.14-2.30 (2H, m), 2.18 (3H, s),2.54-2.65 (2H, m), 2.89-3.06 (4H, m), 3.58 (2H, s), 4.19 (1H, dd, J=8.4,4.4 Hz), 5.66 (1H, d, J=0.8 Hz), 6.79 (1H, d, J=5.2 Hz), 7.06 (1H, d,J=5.2 Hz), 7.22-7.36 (5H, m).

Production Example 1651-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-3-thienyl)ethanol

The title compound (4.17 g, 79% yield) was obtained in the same manneras Production Example 164 from 3.66 g of2-(4-fluoro-3-thienyl)-1-(4-pyridyl)ethanone and 2.36 ml of benzylbromide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.12-2.30 (2H, m), 2.56-2.64 (2H, m),2.73 (1H, dd, J=14.4, 8.4 Hz), 2.82 (1H, dd, J=14.4, 4.4 Hz), 2.96-3.02(2H, m), 3.58 (2H, s), 4.24 (1H, dd, J=8.0, 4.4 Hz), 5.60-5.66 (1H, m),6.67 (1H, d, J=4.0 Hz), 6.98 (1H, t, J=4.0 Hz), 7.22-7.36 (5H, m).

Production Example 1661-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-methyl-2-thienyl)ethanone

The title compound (1.12 g, 40% yield) was obtained in the same manneras Production Example 15 from 2.85 g of1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3-methyl-2-thienyl)ethanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.13 (3H, s), 2.39-2.45 (2H, m), 2.61(2H, t, J=6.0 Hz), 3.19-3.23 (2H, m), 3.62 (2H, s), 4.04 (2H, s), 6.79(1H, d, J=5.2 Hz), 6.88-6.91 (1H, m), 7.08 (1H, d, J=5.2 Hz), 7.23-7.34(5H, m).

Production Example 1671-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-3-thienyl)ethanone

The title compound (1.61 g, 39% yield) was obtained in the same manneras Production Example 15 from 4.17 g of1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-3-thienyl)ethanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.39-2.45 (2H, m), 2.61 (2H, t, J=5.6Hz), 3.19-3.23 (2H, m), 3.63 (2H, s), 3.87 (2H, s), 6.69 (1H, d, J=3.6Hz), 6.87-6.91 (1H, m), 6.99-7.03 (1H, m), 7.25-7.36 (5H, m).

Production Example 168(1-Benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanone

After dissolving 591 mg of 1,3-dihydroisobenzofuran in 10 ml oftetrahydrofuran, 3.9 ml of n-butyllithium (1.5 M, n-hexane solution) wasadded thereto at −70° C. under a nitrogen atmosphere, the mixture wasstirred for 1 hour, and then a solution of 1 g of1-benzylpiperidine-4-carboxaldehyde in tetrahydrofuran (5 ml) was addeddropwise and the mixture was stirred for 1 hour. Water was added to thereaction solution, extraction was performed with ethyl acetate, theextract was dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. Purification was performed bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain 597 mg of(1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanol.

After adding 0.511 ml of dimethylsulfoxide dropwise to a dichloromethanesolution (15 ml) containing 0.315 ml of oxalyl chloride at −70° C., themixture was stirred for 10 minutes, a solution of 597 mg of(1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanol indichloromethane (5 ml) was added dropwise, and stirring was continuedfor 1 hour. Next, 2.5 ml of triethylamine was added dropwise to thereaction solution, the cooling bath was removed, and the mixture wasstirred at room temperature. Water was added to the reaction solution,and extraction was performed with ethyl acetate. After drying overanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure to obtain the title compound (517 mg, 33% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-2.07 (6H, m), 2.76-2.94 (3H, m),3.43-3.51 (2H, m), 5.23-5.34 (2H, m), 5.53-5.56 (1H, m), 7.22-7.35 (9H,m).

Production Example 1691-(tert-Butoxycarbonyl)-4-methyl-4-(methanesulfonyloxymethyl)piperidine

The title compound (3.61 g, 98% yield) was obtained in the same manneras Example 38 from 2.74 g of1-(tert-butoxycarbonyl)-4-fluoro-4-(hydroxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.07 (3H, s), 1.33-1.40 (2H, m),1.43-1.54 (11H, m), 3.02 (3H, s), 3.11-3.19 (2H, m), 3.64-3.73 (2H, m),3.95 (2H, s).

Production Example 1701-(tert-Butoxycarbonyl)-4-(2-fluorophenoxymethyl)-4-methylpiperidine

The title compound (243 mg, 59% yield) was obtained in the same manneras Production Example 41 from 100 mg of 2-fluorophenol and 394 mg of1-(tert-butoxycarbonyl)-4-(methanesulfonyloxymethyl)-4-methylpiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.14 (3H, s), 1.17-1.30 (2H, m), 1.46(9H, s), 1.53-1.67 (2H, m), 3.15-3.25 (2H, m), 3.64-3.75 (2H, m), 3.73(2H, s), 6.85-6.97 (2H, m), 7.01-7.09 (2H, m).

Production Example 171trans-1-[1-(Benzyloxycarbonyl)-2-methylpiperidin-4-yl]-(2-fluorophenyl)ethanone

The title compound (0.79 g, 27% yield) was obtained in the same manneras Production Example 26 from 2.00 g oftrans-1-(benzyloxycarbonyl)-2-methylpiperidine-4-carbonitrile and 2.48 gof 2-fluorobenzyl chloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.17 (3H, d, J=6.8 Hz), 1.48-1.60 (1H,m), 1.67-1.88 (3H, m), 2.77-2.88 (1H, m), 2.88-3.00 (1H, m), 3.78 (2H,s), 4.05-4.24 (1H, m), 4.52-4.68 (1H, m), 5.12 (2H, s), 7.02-7.18 (3H,m), 7.24-7.40 (6H, m).

Production Example 172cis-1-(1-Benzyl-2-methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone

The title compound (373 mg, 44% yield) was obtained in the same manneras Production Example 26 from 563 mg ofcis-1-benzyl-2-methylpiperidine-4-carbonitrile and 1.90 g of2-fluorobenzyl chloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.25 (3H, d, J=6.8 Hz), 1.46-1.67 (2H,m), 1.72-2.00 (3H, m), 2.22-2.32 (1H, m), 2.45-2.57 (1H, m), 2.84-2.93(1H, m), 3.11 (1H, d, J=14.1 Hz), 3.74 (2H, s), 4.11 (1H, d, J=14.1 Hz),6.99-7.39 (9H, m).

Production Example 173trans-1-(2-Methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone

The title compound (547 mg, 100% yield) was obtained in the same manneras Production Example 140 from 0.79 g oftrans-1-[1-(benzyloxycarbonyl)-2-methylpiperidin-4-yl]-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.07 (3H, d, J=6.8 Hz), 1.39-1.48 (1H,m), 1.67-1.91 (2H, m), 1.94-2.07 (2H, m), 2.79-2.96 (4H, m), 3.79 (2H,s), 7.01-7.12 (2H, m), 7.14-7.20 (1H, m), 7.22-7.28 (1H, m).

Production Example 174cis-1-(2-Methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone hydrochloride

The title compound (208 mg, 69% yield) was obtained in the same manneras Production Example 29 from 373 mg ofcis-1-(1-benzyl-2-methylpiperidin-4-yl)-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.26 (3H, d, J=6.4 Hz), 1.37-1.48 (1H,m), 1.55-1.67 (1H, m), 2.00-2.12 (2H, m), 2.85-2.97 (2H, m), 3.10-3.22(1H, m), 3.28-3.35 (1H, m), 3.94 (2H, s), 7.11-7.17 (2H, m), 7.21-7.33(2H, m), 8.56-8.80 (1H, m), 9.10-9.30 (1H, m).

Example 12-Methoxy-3-[4-(2-methylphenoxymethyl)piperidino]methyl-pyrazine

After suspending 200 mg of 4-(2-methylphenoxymethyl)piperidinehydrochloride in 5 ml of dichloromethane, 137 mg of3-methoxypyrazine-2-carboxaldehyde [CAS No. 63874-90-8] and 264 mg ofsodium triacetoxyborohydride were added while stirring, and the stirringwas continued overnight at room temperature. Aqueous sodium carbonatesolution was added to the reaction mixture and extraction was performedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate) to obtainthe title compound (236 mg, 87% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45-1.57 (2H, m), 1.80-1.91 (3H, m),2.13-2.23 (5H, m), 3.04-3.10 (2H, m), 3.71 (2H, s), 3.79 (2H, d, J=6.0Hz), 3.98 (3H, s), 6.78 (1H, d, J=8.0 Hz), 6.84 (1H, dt, J=7.6, 1.2 Hz),7.10-7.16 (2H, m), 7.99 (1H, d, J=2.8 Hz), 8.13 (1H, d, J=2.8 Hz).

Example 2 Ethyl1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-carboxylate

The title compound (275 mg, 48% yield) was obtained in the same manneras Example 1 from 300 mg of 2-methoxypyridine-3-carboxaldehyde and 445mg of 4-(ethoxycarbonyl)-4-(2-phenylethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.29 (3H, t, J=7.2 Hz), 1.53-1.61 (2H,m), 1.79-1.88 (2H, m), 2.06-2.24 (4H, m), 2.49-2.53 (2H, m), 2.70-2.77(2H, m), 3.46 (2H, s), 3.94 (3H, s), 4.18 (2H, q, J=7.2 Hz), 6.86 (1H,dd, J=7.2, 4.8 Hz), 7.12-7.20 (3H, m), 7.27 (2H, t, J=7.6 Hz), 7.62-7.66(1H, m), 8.05 (1H, dd, J=4.8, 2.0 Hz).

Example 31-(2-Methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-methanol

After dissolving 247 mg of ethyl1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-carboxylatein 10 ml of diethyl ether, the solution was cooled to −20° C. and 1 mlof diisobutylaluminium hydride (1.5 M, toluene solution) was addeddropwise. The mixture was stirred for 4 hours while slowly raising thetemperature to room temperature, and then approximately 10 ml of asaturated aqueous solution of potassium sodium (+)-tartrate tetrahydrateand approximately 10 ml of ethyl acetate were added and the mixture wasstirred for 10 minutes at room temperature. The organic layer wasseparated off and the aqueous layer was extracted with ethyl acetate.The organic layers were combined and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by NH silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (173 mg,79% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.53-1.63 (4H, m), 1.65-1.77 (2H, m),2.43-2.59 (6H, m), 3.51 (2H, s), 3.55 (2H, s), 3.94 (3H, s), 6.85-6.89(1H, m), 7.12-7.21 (3H, m), 7.24-7.31 (2H, m), 7.60-7.67 (1H, m), 8.06(1H, dd, J=4.8, 2.0 Hz).

Example 43-[4-(2-Fluorophenoxymethyl)-4-(2-phenylethyl)piperidino]methyl-2-methoxypyridine

After dissolving 55 mg of1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-methanol,51 mg of triphenylphosphine and 20 mg of 2-fluorophenol in 10 ml oftetrahydrofuran, the solution was cooled to 0° C. 0.13 ml of diethylazodicarboxylate (40% toluene solution) was then added dropwise and themixture was stirred overnight at room temperature. After stirring for 5hours at 70° C. and cooling to room temperature, the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (5 mg, 7% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.57-1.64 (2H, m), 1.67-1.72 (2H, m),2.31-2.40 (2H, m), 2.59-2.64 (2H, m), 3.08-3.15 (2H, m), 3.33 (2H, td,J=12.8, 2.8 Hz), 3.63 (2H, s), 3.98 (3H, s), 4.44 (2H, s), 6.98 (1H, dd,J=7.4, 5.0 Hz), 7.16-7.20 (3H, m), 7.25-7.31 (6H, m), 8.09 (1H, dd,J=7.4, 1.6 Hz), 8.21 (1H, dd, J=5.2, 1.6 Hz).

Example 5anti-(E)-3-(5-Chloro-2-methoxy-3-pyridinylmethyl)-9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonane

After adding 150 mg of 2-methoxy-5-chloro-3-(chloromethyl)pyridine, 200mg of anti-(E)-9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonanehydrochloride and 118 mg of anhydrous potassium carbonate to 5 ml ofacetonitrile, the mixture was stirred overnight at room temperature. Thestirring was continued for 2 hours at 60° C., and then ethyl acetate wasadded to the reaction solution, the insoluble portion was filtered offand the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (164 mg, 58%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54-1.65 (3H, m), 1.84-1.89 (2H, m),1.91-2.02 (2H, m), 2.40-2.46 (3H, m), 2.59-2.73 (1H, m), 2.99-3.04 (2H,m), 3.38 (2H, s), 3.94 (3H, s), 6.55-6.66 (2H, m), 7.02 (1H, ddd,J=10.8, 8.0, 1.2 Hz), 7.09 (1H, dt, J=8.0, 1.2 Hz), 7.15-7.21 (1H, m),7.49 (1H, dt, J=8.0, 1.2 Hz), 7.64 (1H, dt, J=2.8, 0.8 Hz), 7.98 (1H, d,J=2.8 Hz).

Example 63-[3-(2-Fluorophenoxymethyl)pyrrolidino]methyl-2-methoxypyrazine

After dissolving 148 mg of 3-methoxypyrazine-2-carboxaldehyde and 200 mgof 3-(2-fluorophenoxymethyl)pyrrolidine in 5 ml of dichloromethane, 0.07ml of acetic acid and 297 mg of sodium triacetoxyborohydride were addedand the mixture was stirred overnight at room temperature. Aqueoussodium carbonate solution was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (245 mg, 77% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60-1.71 (1H, m), 2.05-2.15 (1H, m),2.56 (1H, dd, J=9.6, 6.0 Hz), 2.67-2.82 (3H, m), 2.98 (1H, dd, J=9.6,8.0 Hz), 3.82 (2H, s), 3.96 (2H, d, J=7.6 Hz), 3.98 (3H, s), 6.85-6.91(1H, m), 6.95 (1H, dt, J=8.0, 2.0 Hz), 7.00-7.09 (2H, m), 7.99 (1H, d,J=2.8 Hz), 8.11 (1H, d, J=2.8 Hz).

Example 72-Methoxy-3-[3-(2-methoxyphenoxymethyl)pyrrolidino]methyl-pyrazine

The title compound (352 mg, 92% yield) was obtained in the same manneras Example 6 from 160 mg of 3-methoxypyrazine-2-carboxaldehyde and 313mg of 3-(2-methoxyphenoxymethyl)pyrrolidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59-1.69 (1H, m), 2.04-2.15 (1H, m),2.55 (1H, dd, J=9.6, 5.6 Hz), 2.66-2.84 (3H, m), 2.98 (1H, dd, J=9.6,7.6 Hz), 3.82 (2H, s), 3.84 (3H, s), 3.94 (2H, d, J=7.2 Hz), 3.97 (3H,s), 6.84-6.94 (4H, m), 7.98 (1H, d, J=2.8 Hz), 8.10 (1H, d, J=2.8 Hz).

Example 83-[3-[2-(2-Fluorophenyl)ethyl]pyrrolidino]methyl-2-methoxypyrazine

The title compound (332 mg, 88% yield) was obtained in the same manneras Example 6 from 160 mg of 3-methoxypyrazine-2-carboxaldehyde and 288mg of 3-[2-(2-fluorophenyl)ethyl]pyrrolidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.51 (1H, m), 1.63-1.74 (2H, m),2.01-2.11 (1H, m), 2.16-2.28 (2H, m), 2.51-2.68 (3H, m), 2.85-2.92 (1H,m), 3.00-3.08 (1H, m), 3.79 (2H, s), 3.97 (3H, s), 6.95-7.06 (2H, m),7.11-7.18 (2H, m), 7.98 (1H, d, J=2.8 Hz), 8.10 (1H, d, J=2.8 Hz).

Example 92-Methoxy-3-[3-[2-(2-methoxyphenyl)ethyl]pyrrolidino]methyl-pyrazine

The title compound (314 mg, 88% yield) was obtained in the same manneras Example 6 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 265mg of 3-[2-(2-methoxyphenyl)ethyl]pyrrolidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.52 (1H, m), 1.60-1.72 (2H, m),2.01-2.11 (1H, m), 2.17-2.29 (2H, m), 2.50-2.68 (3H, m), 2.85-2.92 (1H,m), 3.05 (1H, m), 3.79 (2H, s), 3.80 (3H, s), 3.97 (3H, s), 6.82 (1H,dd, J=7.6, 1.2 Hz), 6.86 (1H, dt, J=7.6, 1.2 Hz), 7.10 (1H, dd, J=7.6,2.0 Hz), 7.16 (1H, dt, J=7.6, 2.0 Hz), 7.98 (1H, d, J=2.8 Hz), 8.10 (1H,d, J=2.8 Hz).

Example 102-Methoxy-3-[3-(2-methylphenoxymethyl)pyrrolidino]methyl-pyrazine

The title compound (262 mg, 76% yield) was obtained in the same manneras Example 6 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 248mg of 3-(2-methylphenoxymethyl)pyrrolidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.63-1.72 (1H, m), 2.05-2.15 (1H, m),2.20 (3H, s), 2.52 (1H, dd, J=9.2, 6.8 Hz), 2.62-2.68 (1H, m), 2.70-2.80(1H, m), 2.82-2.88 (1H, m), 3.03 (1H, dd, J=9.2, 8.0 Hz), 3.81 (1H, d,J=14.0 Hz), 3.85 (1H, d, J=14.0 Hz), 3.88-3.94 (2H, m), 3.98 (3H, s),6.79 (1H, dd, J=7.6, 1.2 Hz), 6.84 (1H, dt, J=7.6, 1.2 Hz), 7.10-7.16(2H, m), 7.99 (1H, d, J=2.8 Hz), 8.11 (1H, d, J=2.8 Hz).

Example 11(E)-3-[4-[2-(2-Fluorophenyl)vinyl]piperidino]methyl-2-methoxypyrazine

After dissolving 186 mg of 3-methoxypyrazine-2-carboxaldehyde and 230 mgof (E)-4-[2-(2-fluorophenyl)vinyl]piperidine in 3 ml of1,2-dichloroethane, 0.08 ml of acetic acid and 373 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. Saturated aqueous sodium bicarbonate solution wasadded to the reaction mixture and extraction was performed with ethylacetate. The extract was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (296 mg, 82% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58-1.69 (2H, m), 1.72-1.80 (2H, m),2.12-2.23 (3H, m), 3.02-3.09 (2H, m), 3.70 (2H, s), 3.98 (3H, s), 6.23(1H, dd, J=16.0, 7.2 Hz), 6.54 (1H, d, J=16.0 Hz), 7.00 (1H, ddd,J=10.8, 8.0, 1.2 Hz), 7.06 (1H, dt, J=8.0, 1.2 Hz), 7.12-7.19 (1H, m),7.43 (1H, dt, J=8.0, 1.6 Hz), 8.00 (1H, d, J=2.4 Hz), 8.13 (1H, d, J=2.4Hz).

Example 122-[1-(3-Methoxy-2-pyrazinylmethyl)piperidin-4-yl]-1-(2-fluorophenyl)ethanone

After adding 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 340 mg of1-(2-fluorophenyl)-2-(piperidin-4-yl)ethanone hydrochloride to 5 ml of1,2-dichloroethane, 350 mg of sodium triacetoxyborohydride was added andthe mixture was stirred for 4 hours at room temperature. Aqueous sodiumcarbonate solution was added to the reaction mixture and extraction wasperformed with ethyl acetate. The organic layer was washed with waterand saturated brine in that order and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (268 mg, 71%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.50 (2H, m), 1.68-1.76 (2H, m),1.93-2.06 (1H, m), 2.11-2.20 (2H, m), 2.89 (2H, dd, J=6.8, 3.2 Hz),2.96-3.02 (2H, m), 3.68 (2H, s), 3.97 (3H, s), 7.12 (1H, ddd, J=11.2,8.4, 1.2 Hz), 7.23 (1H, ddd, J=8.4, 8.0, 1.2 Hz), 7.47-7.54 (1H, m),7.82 (1H, dt, J=7.6, 2.0 Hz), 7.98 (1H, d, J=2.8 Hz), 8.11 (1H, d, J=2.8Hz).

Example 133-[4-[2-(Benzofuran-7-yl)ethyl]piperidino]methyl-2-methoxypyrazine

After adding 124 mg of 3-methoxypyrazine-2-carboxaldehyde and 200 mg of4-[2-(benzofuran-7-yl)ethyl]piperidine hydrochloride to 3 ml oftetrahydrofuran, 238 mg of sodium triacetoxyborohydride was added andthe mixture was stirred overnight at room temperature. Aqueous sodiumcarbonate solution was added to the reaction mixture and extraction wasperformed with ethyl acetate. The organic layer was washed with waterand saturated brine in that order and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (218 mg, 82%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.25-1.47 (3H, m), 1.65-1.80 (4H, m),2.04-2.13 (2H, m), 2.88-2.94 (2H, m), 2.98-3.04 (2H, m), 3.67 (2H, s),3.97 (3H, s), 6.75 (1H, d, J=2.0 Hz), 7.08 (1H, dd, J=7.2, 1.2 Hz), 7.15(1H, t, J=7.2 Hz), 7.43 (1H, dd, J=7.2, 1.2 Hz), 7.60 (1H, d, J=2.0 Hz),7.98 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 143-[4-(2-Fluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine

The title compound (72 mg, 74% yield) was obtained in the same manner asExample 13 from 60 mg of 3-methoxypyrazine-2-carboxaldehyde and 72 mg of4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.60 (2H, m), 1.81-1.94 (3H, m),2.12-2.20 (2H, m), 3.02-3.10 (2H, m), 3.70 (2H, s), 3.85 (2H, d, J=6.4Hz), 3.98 (3H, s), 6.84-6.90 (1H, m), 6.94 (1H, td, J=8.2, 1.6 Hz),7.00-7.09 (2H, m), 7.99 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 153-[4-(2,5-Difluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine

The title compound (309 mg, 80% yield) was obtained in the same manneras Example 1 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 343mg of 4-(2,5-difluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.56 (2H, m), 1.80-1.94 (3H, m),2.12-2.20 (2H, m), 3.04-3.10 (2H, m), 3.70 (2H, s), 3.82 (2H, d, J=6.4Hz), 3.98 (3H, s), 6.52-6.58 (1H, m), 6.66 (1H, ddd, J=9.6, 8.8, 3.2Hz), 6.99 (1H, ddd, J=10.8, 8.8, 4.2 Hz), 7.99 (1H, d, J=2.8 Hz), 8.13(1H, d, J=2.8 Hz).

Example 16 2-Methoxy-3-[4-(2-methylbenzyloxy)piperidino]methyl-pyrazine

The title compound (306 mg, 81% yield) was obtained in the same manneras Example 6 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 340mg of 4-(2-methylbenzyloxy)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.70-1.81 (2H, m), 1.91-1.99 (2H, m),2.28-2.37 (5H, m), 2.85-2.93 (2H, m), 3.41-3.48 (1H, m), 3.69 (2H, s),3.97 (3H, s), 4.51 (2H, s), 7.13-7.22 (3H, m), 7.31-7.35 (1H, m), 7.99(1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 172-Methoxy-3-[4-(3-methylphenoxymethyl)piperidino]methylpyrazine

The title compound (217 mg, 60% yield) was obtained in the same manneras Example 1 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 314mg of 4-(3-methylphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.55 (2H, m), 1.75-1.86 (3H, m),2.11-2.19 (2H, m), 2.32 (3H, s), 3.03-3.09 (2H, m), 3.70 (2H, s), 3.78(2H, d, J=6.0 Hz), 3.98 (3H, s), 6.66-6.76 (3H, m), 7.15 (1H, t, J=7.6Hz), 7.99 (1H, d, J=2.8 Hz), 8.13 (1H, d, J=2.8 Hz).

Example 182-Methoxy-3-[4-(3-methoxyphenoxymethyl)piperidino]methyl-pyrazine

The title compound (278 mg, 74% yield) was obtained in the same manneras Example 1 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 335mg of 4-(3-methoxyphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.55 (2H, m), 1.75-1.88 (3H, m),2.11-2.20 (2H, m), 3.03-3.09 (2H, m), 3.70 (2H, s), 3.77 (2H, d, J=5.2Hz), 3.78 (3H, s), 3.98 (3H, s), 6.43-6.52 (3H, m), 7.16 (1H, t, J=8.0Hz), 7.99 (1H, d, J=2.8 Hz), 8.13 (1H, d, J=2.8 Hz).

Example 192-Methoxy-3-[4-[2-(trifluoromethyl)phenoxymethyl]piperidino]methyl-pyrazine

The title compound (255 mg, 63% yield) was obtained in the same manneras Example 1 from 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 384mg of 4-[2-(trifluoromethyl)phenoxymethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.53 (2H, m), 1.80-1.94 (3H, m),2.13-2.20 (2H, m), 3.04-3.10 (2H, m), 3.71 (2H, s), 3.86 (2H, d, J=6.4Hz), 3.98 (3H, s), 6.93-7.01 (2H, m), 7.46 (1H, t, J=7.6 Hz), 7.55 (1H,d, J=7.6 Hz), 7.99 (1H, d, J=2.8 Hz), 8.13 (1H, d, J=2.8 Hz).

Example 202-tert-Butylthio-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (205 mg, 57% yield) was obtained in the same manneras Example 1 from 180 mg of 3-(tert-butylthio)pyrazine-2-carboxaldehydeand 248 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.52 (2H, m), 1.59 (9H, s),1.79-1.94 (3H, m), 2.12-2.20 (2H, m), 2.95-3.02 (2H, m), 3.64 (2H, s),3.85 (2H, d, J=6.4 Hz), 6.84-6.90 (1H, m), 6.94 (1H, dt, J=8.8, 1.6 Hz),7.01-7.09 (2H, m), 8.21 (1H, d, J=2.8 Hz), 8.23 (1H, d, J=2.8 Hz).

Example 21(E)-2-Methoxy-3-[4-[2-(3-methyl-2-thienyl)vinyl]piperidino]methyl-pyrazine

After dissolving 139 mg of (E)-4-[2-(3-methyl-2-thienyl)vinyl]piperidinein 7 ml of tetrahydrofuran, 111 mg of 3-methoxypyrazine-2-carboxaldehydeand 213 mg of sodium triacetoxyborohydride were added while stirring,and the stirring was continued overnight at room temperature. A 1Nsodium hydroxide solution was added to the reaction mixture to render italkaline, and then extraction was performed with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by NH silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (120 mg, 54% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54-1.66 (2H, m), 1.69-1.78 (2H, m),2.06-2.24 (3H, m), 2.19 (3H, s), 3.00-3.08 (2H, m), 3.69 (2H, s), 3.98(3H, s), 5.94 (1H, dd, J=16.0, 7.0 Hz), 6.49 (1H, d, J=16.0 Hz), 6.75(1H, d, J=5.2 Hz), 6.98 (1H, d, J=5.2 Hz), 7.99 (1H, d, J=2.8 Hz), 8.13(1H, d, J=2.8 Hz).

Example 223-[3-[2-(2-Fluorophenyl)ethyl]piperidino]methyl-2-methoxypyrazine

The title compound (159 mg, 57% yield) was obtained in the same manneras Example 1 from 141 mg of 3-methoxypyrazine-2-carboxaldehyde and 208mg of 3-[2-(2-fluorophenyl)ethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.85-0.96 (1H, m), 1.41-1.56 (2H, m),1.58-1.72 (3H, m), 1.76-1.87 (2H, m), 2.00-2.08 (1H, m), 2.56-2.70 (2H,m), 2.92-3.03 (2H, m), 3.67 (2H, s), 3.97 (3H, s), 6.94-7.05 (2H, m),7.10-7.18 (2H, m), 7.99 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 233-[3-[2-(2-Methoxyphenyl)ethyl]piperidino]methyl-2-methoxypyrazine

The title compound (269 mg, 86% yield) was obtained in the same manneras Example 21 from 153 mg of 3-methoxypyrazine-2-carboxaldehyde and 202mg of 3-[2-(2-methoxyphenyl)ethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.82-0.95 (1H, m), 1.37-1.52 (2H, m),1.59-1.73 (3H, m), 1.75-1.88 (2H, m), 1.98-2.07 (1H, m), 2.52-2.67 (2H,m), 2.92-3.06 (2H, m), 3.67 (2H, d, J=1.6 Hz), 3.80 (3H, s), 3.97 (3H,s), 6.82 (1H, d, J=7.6 Hz), 6.86 (1H, td, J=7.6, 1.2 Hz), 7.09 (1H, dd,J=7.6, 1.6 Hz), 7.15 (1H, td, J=7.6, 1.6 Hz), 7.98 (1H, d, J=2.8 Hz),8.12 (1H, d, J=2.8 Hz).

Example 242-Methoxy-3-[3-(2-methylphenoxymethyl)piperidino]methyl-pyrazine

The title compound (140 mg, 47% yield) was obtained in the same manneras Example 1 from 151 mg of 3-methoxypyrazine-2-carboxaldehyde and 221mg of 3-(2-methylphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.10-1.22 (1H, m), 1.67-1.76 (2H, m),1.78-1.86 (1H, m), 1.98-2.07 (1H, m), 2.09-2.28 (2H, m), 2.17 (3H, s),2.93-3.00 (1H, m), 3.14-3.20 (1H, m), 3.71 (2H, d, J=2.8 Hz), 3.77 (1H,dd, J=9.2, 7.2 Hz), 3.83 (1H, dd, J=9.2, 5.6 Hz), 3.96 (3H, s), 6.76(1H, d, J=7.4 Hz), 6.83 (1H, td, J=7.4, 1.0 Hz), 7.09-7.15 (2H, m), 7.99(1H, d, J=2.8 Hz), 8.11 (1H, d, J=2.8 Hz).

Example 253-[4-[2-(2-Methoxyphenoxy)ethyl]piperidino]methyl-2-methoxypyrazine

The title compound (180 mg, 59% yield) was obtained in the same manneras Example 1 from 141 mg of 3-methoxypyrazine-2-carboxaldehyde and 231mg of 4-[2-(2-methoxyphenoxy)ethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.48 (2H, m), 1.50-1.62 (1H, m),1.68-1.76 (2H, m), 1.80 (2H, q, J=6.8 Hz), 2.07-2.16 (2H, m), 2.97-3.05(2H, m), 3.67 (2H, s), 3.86 (3H, s), 3.97 (3H, s), 4.05 (2H, t, J=6.8Hz), 6.86-6.94 (4H, m), 7.98 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 263-[3-(2-Fluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine

The title compound (170 mg, 62% yield) was obtained in the same manneras Example 1 from 144 mg of 3-methoxypyrazine-2-carboxaldehyde and 205mg of 3-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.10-1.22 (1H, m), 1.64-1.73 (2H, m),1.78-1.86 (1H, m), 2.03-2.12 (1H, m), 2.12-2.29 (2H, m), 2.88-2.95 (1H,m), 3.07-3.14 (1H, m), 3.70 (2H, s), 3.85-3.93 (2H, m), 3.96 (3H, s),6.84-6.96 (2H, m), 7.00-7.08 (2H, m), 7.99 (1H, d, J=2.8 Hz), 8.10 (1H,d, J=2.8 Hz).

Example 272-Methoxy-3-[3-(2-methoxyphenoxymethyl)piperidino]methyl-pyrazine

The title compound (309 mg, 80% yield) was obtained in the same manneras Example 21 from 181 mg of 3-methoxypyrazine-2-carboxaldehyde and 247mg of 3-(2-methoxyphenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.07-1.18 (1H, m), 1.62-1.72 (2H, m),1.80-1.88 (1H, m), 1.98-2.32 (3H, m), 2.87-2.95 (1H, m), 3.10-3.16 (1H,m), 3.67 (1H, d, J=13.2 Hz), 3.72 (1H, d, J=13.2 Hz), 3.83 (3H, s),3.84-3.90 (2H, m), 3.96 (3H, s), 6.85-6.92 (4H, m), 7.98 (1H, d, J=2.8Hz), 8.10 (1H, d, J=2.8 Hz).

Example 281-(2-Methoxyphenyl)-2-[1-(3-methoxypyrazin-2-yl)methylpiperidin-4-yl]ethanone

The title compound (211 mg, 67% yield) was obtained in the same manneras Example 21 from 146 mg of 3-methoxypyrazine-2-carboxaldehyde and 206mg of 1-(2-methoxyphenyl)-2-(piperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.47 (2H, m), 1.66-1.74 (2H, m),1.90-2.02 (1H, m), 2.09-2.18 (2H, m), 2.89 (2H, d, J=6.8 Hz), 2.94-3.01(2H, m), 3.67 (2H, s), 3.88 (3H, s), 3.97 (3H, s), 6.95 (1H, d, J=8.4Hz), 6.99 (1H, td, J=7.4, 1.2 Hz), 7.44 (1H, ddd, J=8.4, 7.4, 1.8 Hz),7.60 (1H, dd, J=7.4, 1.8 Hz), 7.98 (1H, d, J=2.8 Hz), 8.11 (1H, d, J=2.8Hz).

Example 292-Methoxy-3-[4-(2-methoxyphenoxymethyl)piperidino]methyl-pyrazine

The title compound (148 mg, 52% yield) was obtained in the same manneras Example 1 from 138 mg of 3-methoxypyrazine-2-carboxaldehyde and 215mg of 4-(2-methoxyphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.54 (2H, m), 1.82-1.98 (3H, m),2.11-2.20 (2H, m), 3.02-3.09 (2H, m), 3.69 (2H, s), 3.85 (2H, d, J=6.8Hz), 3.85 (3H, s), 3.98 (3H, s), 6.85-6.94 (4H, m), 7.99 (1H, d, J=2.8Hz), 8.12 (1H, d, J=2.8 Hz).

Example 303-(2-Fluorobenzyl)-8-(2-methoxy-3-pyridinylmethyl)-1-oxa-3,8-diazaspiro[4.5]deca-2-one

The title compound (14 mg, 27% yield) was obtained in the same manner asExample 1 from 21 mg of 2-methoxypyridine-3-carboxaldehyde and 41 mg of3-(2-fluorobenzyl)-1-oxa-3,8-diazaspiro[4.5]deca-2-one hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.70-1.80 (2H, m), 1.88-1.95 (2H, m),2.52-2.65 (4H, m), 3.19 (2H, s), 3.52 (2H, s), 3.94 (3H, s), 4.50 (2H,s), 6.86 (1H, dd, J=7.2, 5.2 Hz), 7.07 (1H, ddd, J=9.8, 8.4, 1.2 Hz),7.14 (1H, td, J=3.6, 1.2 Hz), 7.27-7.37 (2H, m), 7.59 (1H, dd, J=7.2,2.0 Hz), 8.06 (1H, dd, J=7.2, 2.0 Hz).

Example 31 3-[4-(2-Fluorobenzyloxy)piperidino]methyl-2-methoxypyrazine

The title compound (210 mg, 73% yield) was obtained in the same manneras Example 1 from 148 mg of 3-methoxypyrazine-2-carboxaldehyde and 212mg of 4-(2-fluorobenzyloxy)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.70-1.80 (2H, m), 1.90-1.99 (2H, m),2.28-2.37 (2H, m), 2.84-2.93 (2H, m), 3.42-3.49 (1H, m), 3.69 (2H, s),3.97 (3H, s), 4.60 (2H, s), 7.02 (1H, ddd, J=9.6, 8.0, 1.0 Hz), 7.13(1H, td, J=8.0, 1.0 Hz), 7.22-7.28 (1H, m), 7.45 (1H, td, J=8.0, 2.0Hz), 7.99 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 323-[4-[2-(2,3-Dihydrobenzofuran-7-yl)ethyl]piperidino]methyl-2-methoxypyrazine

The title compound (249 mg, 79% yield) was obtained in the same manneras Example 21 from 153 mg of 3-methoxypyrazine-2-carboxaldehyde and 207mg of 4-[2-(2,3-dihydrobenzofuran-7-yl)ethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.22-1.43 (3H, m), 1.50-1.60 (2H, m),1.68-1.76 (2H, m), 2.03-2.12 (2H, m), 2.53-2.60 (2H, m), 2.97-3.03 (2H,m), 3.20 (2H, t, J=8.8 Hz), 3.66 (2H, s), 3.97 (3H, s), 4.53 (2H, t,J=8.8 Hz), 6.76 (1H, t, J=7.4 Hz), 6.90-6.94 (1H, m), 7.03 (1H, dd,J=7.4, 1.2 Hz), 7.98 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 332-tert-Butoxy-3-[3-[2-(2-fluorophenoxy)ethyl]azetidin-1-yl]methyl-pyrazine

The title compound (54 mg, 39% yield) was obtained in the same manner asExample 21 from 84 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 76mg of 3-[2-(2-fluorophenoxy)ethyl]azetidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 2.08 (2H, q, J=6.4 Hz),2.72-2.82 (1H, m), 3.07 (2H, t, J=7.6 Hz), 3.70 (2H, t, J=7.6 Hz), 3.72(2H, s), 3.99 (2H, t, J=6.4 Hz), 6.85-6.96 (2H, m), 7.01-7.09 (2H, m),7.89 (1H, d, J=2.8 Hz), 8.00 (1H, d, J=2.8 Hz).

Example 342-tert-Butoxy-3-[4-(2-chlorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (229 mg, 71% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and260 mg of 4-(2-chlorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.55 (2H, m), 1.60 (9H, s),1.83-1.94 (3H, m), 2.13-2.22 (2H, m), 3.01-3.07 (2H, m), 3.67 (2H, s),3.85 (2H, d, J=6.0 Hz), 6.84-6.91 (2H, m), 7.19 (1H, ddd, J=8.4, 7.6,1.6 Hz), 7.34 (1H, dd, J=7.6, 1.2 Hz), 7.92 (1H, d, J=2.8 Hz), 8.05 (1H,d, J=2.8 Hz).

Example 352-tert-Butoxy-3-[4-(3-fluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (223 mg, 72% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and243 mg of 4-(3-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.53 (2H, m), 1.60 (9H, s),1.74-1.84 (3H, m), 2.11-2.19 (2H, m), 3.01-3.07 (2H, m), 3.65 (2H, s),3.77 (2H, d, J=6.0 Hz), 6.56-6.68 (3H, m), 7.20 (1H, dt, J=8.4, 6.8 Hz),7.92 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 362-tert-Butoxy-3-[4-(2,4-difluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (183 mg, 56% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and261 mg of 4-(2,4-difluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.52 (2H, m), 1.60 (9H, s),1.78-1.86 (3H, m), 2.11-2.19 (2H, m), 3.00-3.07 (2H, m), 3.65 (2H, s),3.81 (2H, d, J=6.0 Hz), 6.73-6.79 (1H, m), 6.81-6.92 (2H, m), 7.92 (1H,d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 372-tert-Butoxy-3-[4-(2-ethoxyphenoxymethyl)piperidino]methyl-pyrazine

The title compound (178 mg, 54% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and270 mg of 4-(2-ethoxyphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.51 (2H, m), 1.41 (3H, t, J=6.8Hz), 1.60 (9H, s), 1.82-1.94 (3H, m), 2.11-2.20 (2H, m), 3.00-3.06 (2H,m), 3.65 (2H, s), 3.83 (2H, d, J=6.8 Hz), 4.06 (2H, q, J=6.8 Hz), 6.88(4H, s), 7.92 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 382-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzonitrile

The title compound (180 mg, 57% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and250 mg of 4-(2-cyanophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.52 (2H, m), 1.61 (9H, s),1.85-1.97 (3H, m), 2.13-2.22 (2H, m), 3.01-3.08 (2H, m), 3.66 (2H, s),3.88 (2H, d, J=6.4 Hz), 6.94 (1H, d, J=8.4 Hz), 6.98 (1H, t, J=7.6 Hz),7.51 (1H, ddd, J=8.4, 7.6, 1.2 Hz), 7.55 (1H, dd, J=7.6, 1.2 Hz), 7.93(1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 392-tert-Butoxy-3-[4-[2-(trifluoromethoxy)phenoxymethyl]piperidino]methyl-pyrazine

The title compound (292 mg, 80% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and270 mg of 4-[2-(trifluoromethoxy)phenoxymethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.52 (2H, m), 1.60 (9H, s),1.80-1.92 (3H, m), 2.13-2.22 (2H, m), 3.00-3.07 (2H, m), 3.66 (2H, s),3.83 (2H, d, J=6.4 Hz), 6.92 (1H, dt, J=8.0, 1.2 Hz), 6.96 (1H, dd,J=8.4, 1.2 Hz), 7.19-7.25 (2H, m), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d,J=2.8 Hz).

Example 402-tert-Butoxy-3-[4-[(2-fluorophenyl)ethynyl]piperidino]methyl-pyrazine

The title compound (338 mg, 84% yield) was obtained in the same manneras Example 6 from 200 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and269 mg of 4-[(2-fluorophenyl)ethynyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.75-1.87 (2H, m),1.92-2.00 (2H, m), 2.34-2.44 (2H, m), 2.62-2.71 (1H, m), 2.83-2.91 (2H,m), 3.65 (2H, s), 7.01-7.08 (2H, m), 7.21-7.26 (1H, m), 7.38 (1H, dd,J=7.6, 2.0 Hz), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 41(E)-2-tert-Butoxy-3-[4-[2-(2-methylphenyl)vinyl]piperidino]methyl-pyrazine

The title compound (289 mg, 95% yield) was obtained in the same manneras Example 6 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of (E)-4-[2-(2-methylphenyl)vinyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.56-1.68 (2H, m), 1.61 (9H, s),1.72-1.79 (2H, m), 2.10-2.23 (3H, m), 2.31 (3H, s), 3.00-3.06 (2H, m),3.66 (2H, s), 6.04 (1H, dd, J=16.0, 7.2 Hz), 6.56 (1H, dd, J=16.0, 0.8Hz), 7.08-7.17 (3H, m), 7.40 (1H, d, J=6.8 Hz), 7.93 (1H, d, J=2.8 Hz),8.06 (1H, d, J=2.8 Hz).

Example 422-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-1-(2-chlorophenyl)ethanone

The title compound (224 mg, 67% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and271 mg of 1-(2-chlorophenyl)-2-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.47 (2H, m), 1.59 (9H, s),1.69-1.77 (2H, m), 1.92-2.03 (1H, m), 2.15 (2H, dt, J=12.0, 2.4 Hz),2.86 (2H, d, J=6.8 Hz), 2.93-2.99 (2H, m), 3.62 (2H, s), 7.28-7.42 (4H,m), 7.91 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 43(E)-2-tert-Butoxy-3-[4-[2-(3-fluorophenyl)vinyl]piperidino]methyl-pyrazine

The title compound (191 mg, 71% yield) was obtained in the same manneras Example 1 from 177 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and146 mg of (E)-4-[2-(3-fluorophenyl)vinyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54-1.66 (2H, m), 1.61 (9H, s),1.70-1.78 (2H, m), 2.08-2.23 (3H, m), 3.00-3.06 (2H, m), 3.66 (2H, s),6.18 (1H, dd, J=16.0, 7.2 Hz), 6.33 (1H, d, J=16.0 Hz), 6.88 (1H, dt,J=8.8, 2.0 Hz), 7.04 (1H, dt, J=10.4, 2.0 Hz), 7.09 (1H, d, J=7.6 Hz),7.21-7.27 (1H, m), 7.94 (1H, d, J=2.8 Hz), 8.06 (1H, d, J=2.8 Hz).

Example 442-tert-Butoxy-3-[4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-pyrazine

The title compound (275 mg, 75% yield) was obtained in the same manneras Example 1 from 180 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and257 mg of 4-[2-(2-fluorophenyl)ethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.20-1.44 (3H, m), 1.50-1.58 (2H, m),1.60 (9H, s), 1.68-1.76 (2H, m), 2.04-2.13 (2H, m), 2.60-2.67 (2H, m),2.95-3.02 (2H, m), 3.63 (2H, s), 6.98 (1H, ddd, J=10.4, 8.0, 1.2 Hz),7.04 (1H, dt, J=7.6, 2.0 Hz), 7.11-7.19 (2H, m), 7.91 (1H, d, J=2.8 Hz),8.04 (1H, d, J=2.8 Hz).

Example 45 2-tert-Butoxy-3-[4-(phenoxymethyl)piperidino]methyl-pyrazine

The title compound (217 mg, 74% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and209 mg of 4-(phenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.54 (2H, m), 1.60 (9H, s),1.75-1.86 (3H, m), 2.11-2.20 (2H, m), 3.01-3.07 (2H, m), 3.65 (2H, s),3.79 (2H, d, J=6.0 Hz), 6.86-6.95 (3H, m), 7.24-7.30 (2H, m), 7.92 (1H,d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 462-tert-Butoxy-3-[4-(4-fluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (204 mg, 66% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and226 mg of 4-(4-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.53 (2H, m), 1.60 (9H, s),1.70-1.84 (3H, m), 2.11-2.19 (2H, m), 3.01-3.07 (2H, m), 3.65 (2H, s),3.74 (2H, d, J=6.0 Hz), 6.77-6.84 (2H, m), 6.92-6.98 (2H, m), 7.92 (1H,d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 472-tert-Butoxy-3-[4-(2,6-difluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (214 mg, 66% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and242 mg of 4-(2,6-difluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.50 (2H, m), 1.60 (9H, s),1.74-1.88 (3H, m), 2.11-2.19 (2H, m), 2.99-3.06 (2H, m), 3.65 (2H, s),3.95 (2H, d, J=6.4 Hz), 6.82-6.96 (3H, m), 7.92 (1H, d, J=2.8 Hz), 8.05(1H, d, J=2.8 Hz).

Example 482-tert-Butoxy-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-quinoxaline

The title compound (174 mg, 63% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxyquinoxaline-2-carboxaldehydeand 176 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.56 (2H, m), 1.71 (9H, s),1.82-1.94 (3H, m), 2.19-2.28 (2H, m), 3.12-3.19 (2H, m), 3.81 (2H, s),3.86 (2H, d, J=6.4 Hz), 6.84-6.90 (1H, m), 6.95 (1H, dt, J=8.0, 1.6 Hz),7.01-7.09 (2H, m), 7.49 (1H, ddd, J=8.4, 7.2, 1.6 Hz), 7.58 (1H, ddd,J=8.4, 7.2, 1.6 Hz), 7.76 (1H, ddd, J=7.2, 1.6, 0.4 Hz), 8.00 (1H, ddd,J=7.2, 1.6, 0.4 Hz).

Example 491-[1-(3-tert-Butoxy-2-quinoxalinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (150 mg, 53% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxyquinoxaline-2-carboxaldehydeand 185 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.70 (9H, s), 1.75-1.92 (4H, m),2.21-2.30 (2H, m), 2.42-2.51 (1H, m), 3.10-3.17 (2H, m), 3.78 (4H, s),7.01-7.11 (2H, m), 7.16 (1H, dt, J=7.6, 2.8 Hz), 7.21-7.28 (1H, m), 7.50(1H, ddd, J=8.4, 7.2, 1.2 Hz), 7.59 (1H, ddd, J=8.4, 7.2, 1.2 Hz), 7.76(1H, dd, J=8.4, 1.2 Hz), 7.99 (1H, dd, J=8.4, 1.2 Hz).

Example 502-tert-Butoxy-3-[4-[2-(2-fluorophenyl)-1-methoxyethyl]piperidino]methyl-pyrazine

The title compound (138 mg, 80% yield) was obtained in the same manneras Example 21 from 93 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and102 mg of 4-[2-(2-fluorophenyl)-1-methoxyethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.68 (4H, m), 1.60 (9H, s),1.76-1.82 (1H, m), 2.02-2.10 (2H, m), 2.67 (1H, dd, J=14.4, 8.8 Hz),2.90 (1H, dd, J=14.4, 5.6 Hz), 3.00-3.08 (2H, m), 3.14-3.21 (1H, m),3.18 (3H, s), 3.63 (2H, s), 7.00 (1H, ddd, J=9.2, 8.0, 1.2 Hz), 7.05(1H, td, J=7.4, 1.2 Hz), 7.15-7.22 (1H, m), 7.22-7.27 (1H, m), 7.92 (1H,d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 511-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-3-yl]-2-(2-fluorophenyl)ethanone

2-(2-Fluorophenyl)-1-(piperidin-3-yl)ethanone (398 mg, 100% yield) wasobtained in the same manner as Production Example 116 from 564 mg of1-[1-(tert-butoxycarbonyl)piperidin-3-yl]-2-(2-fluorophenyl)ethanone.

The title compound (193 mg, 69% yield) was then obtained in the samemanner as Example 21 from 156 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 160 mg of2-(2-fluorophenyl)-1-(piperidin-3-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.47 (1H, m), 1.55-1.77 (2H, m),1.59 (9H, s), 1.88-1.96 (1H, m), 2.09-2.18 (1H, m), 2.25-2.34 (1H, m),2.79-2.83 (2H, m), 3.04-3.10 (1H, m), 3.66 (2H, s), 3.75 (2H, s), 7.03(1H, ddd, J=9.6, 7.8, 1.2 Hz), 7.07 (1H, td, J=7.8, 1.2 Hz), 7.12 (1H,td, J=7.8, 2.0 Hz), 7.20-7.28 (1H, m), 7.93 (1H, d, J=2.8 Hz), 8.04 (1H,d, J=2.8 Hz).

Example 522-tert-Butoxy-3-[4-(2-methyl-5-phenylpyrrol-1-yl)methyl-piperidino]methyl-pyrazine

The title compound (110 mg, 65% yield) was obtained in the same manneras Example 6 from 160 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and103 mg of 4-(2-phenyl-5-methylpyrrol-1-yl)methyl-piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.08 (2H, ddd, J=25, 12.4, 4 Hz),1.23-1.29 (2H, m), 1.34-1.48 (1H, m), 1.55 (9H, s), 1.85 (2H, td,J=11.8, 2.4 Hz), 2.29 (3H, s), 2.83 (2H, d, J=11.6 Hz), 3.52 (2H, s),3.83 (2H, d, J=11.2 Hz), 5.94 (1H, d, J=3.2 Hz), 6.06 (1H, d, J=3.2 Hz),7.23-7.28 (1H, m), 7.30-7.38 (4H, m), 7.88 (1H, d, J=2.6 Hz), 8.00 (1H,d, J=2.6 Hz).

Example 532-tert-Butoxy-3-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidino]methyl-pyrazine

The title compound (60 mg, 32% yield) was obtained in the same manner asExample 1 from 105 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 115mg of 4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 2.02-2.17 (4H, m), 2.34(2H, td, J=11.2, 2.8 Hz), 2.96-3.04 (1H, m), 3.04-3.09 (2H, m), 3.68(2H, s), 7.44-7.52 (3H, m), 7.95 (1H, d, J=2.8 Hz), 8.04-8.09 (3H, m).

Example 542-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-4-fluoro-2,3-dihydro-isoindol-1-one

The title compound (40 mg, 17% yield) was obtained in the same manner asExample 6 from 129 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 148mg of 4-fluoro-2-(piperidin-4-yl)-2,3-dihydroisoindol-1-one.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.78-1.83 (2H, m), 1.92(2H, ddd, J=15.6, 12.0, 3.6 Hz), 2.33 (2H, td, J=11.8, 2.2 Hz),3.08-3.15 (2H, m), 3.69 (2H, s), 4.29 (1H, tt, J=12.0, 4.4 Hz), 4.35(2H, s), 7.08 (1H, t, J=8.8 Hz), 7.22 (1H, d, J=7.2 Hz), 7.43-7.54 (1H,m), 7.94 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=2.4 Hz).

Example 552-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methyl-4-fluoro-isoindole-1,3-dione

The title compound (76 mg, 36% yield) was obtained in the same manner asExample 1 from 109 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 150mg of 4-fluoro-2-(piperidin-4-ylmethyl)isoindole-1,3-dionehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43 (2H, ddd, J=24.8, 12.8, 3.6 Hz),1.58 (9H, s), 1.60-1.66 (1H, m), 1.70-1.84 (2H, m), 2.07 (2H, td,J=11.6, 2.2 Hz), 2.94-3.20 (2H, m), 3.58 (2H, d, J=6.8 Hz), 3.61 (2H,s), 7.34-7.39 (1H, m), 7.65 (1H, d, J=6.4 Hz), 7.71 (1H, ddd, J=8.4,7.6, 4.4 Hz), 7.90 (1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 562-tert-Butoxy-3-[4-[3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-pyrazine

The title compound (61 mg, 61% yield) was obtained in the same manner asExample 1 from 57 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 69 mgof 4-[3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 2.03-2.17 (4H, m), 2.34(2H, td, J=11.4, 3.0 Hz), 2.97-3.10 (3H, m), 3.69 (2H, s), 7.22 (1H,ddd, J=10.4, 8.0, 1.0 Hz), 7.27 (1H, td, J=8.0, 1.4 Hz), 7.45-7.51 (1H,m), 7.95 (1H, d, J=2.4 Hz), 8.02-8.07 (2H, m).

Example 572-tert-Butoxy-3-[4-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-pyrazine

The title compound (12 mg, 17% yield) was obtained in the same manner asExample 1 from 41 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 50 mgof 4-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 2.01-2.16 (4H, m), 2.34(2H, td, J=11.4, 3.0 Hz), 2.96-3.04 (1H, m), 3.04-3.10 (2H, m), 3.69(2H, s), 7.19 (1H, tdd, J=8.4, 2.8, 1.2 Hz), 7.44 (1H, td, J=7.8, 5.6Hz), 7.77 (1H, ddd, J=6.2, 2.4, 1.2 Hz), 7.86 (1H, ddd, J=8.0, 1.6, 1.2Hz), 7.95 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 582-tert-Butoxy-3-[4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-pyrazine

The title compound (16 mg, 50% yield) was obtained in the same manner asExample 1 from 22 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 22 mgof 4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 2.01-2.15 (4H, m), 2.32(2H, td, J=11.6, 2.8 Hz), 2.95-3.03 (1H, m), 3.04-3.12 (2H, m), 3.69(2H, s), 7.13-7.19 (2H, m), 7.95 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8Hz), 8.06-8.09 (2H, m).

Example 592-tert-Butoxy-3-[2-[2-(2-fluorophenoxy)ethyl]piperidino]methyl-pyrazine

The title compound (15 mg, 14% yield) was obtained in the same manner asExample 6 from 63 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 60 mgof 2-[2-(2-fluorophenoxy)ethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.36-1.62 (3H, m),1.63-1.81 (3H, m), 1.99-2.08 (1H, m), 2.26-2.34 (1H, m), 2.39 (1H,quintet, J=6.2 Hz), 2.68-2.73 (1H, m), 2.95 (1H, tt, J=12.4, 4.8 Hz),3.61 (1H, d, J=13.6 Hz), 3.97 (1H, d, J=13.6 Hz), 4.07-4.13 (2H, m),6.82-6.88 (1H, m), 6.93-7.07 (3H, m), 7.87 (1H, d, J=2.8 Hz), 7.98 (1H,d, J=2.8 Hz).

Example 601-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

After suspending 295 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride in 6 ml of dichloromethane, 247 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 364 mg of sodiumtriacetoxyborohydride were added while stirring on ice, and the stirringwas continued for 3.5 days at room temperature. A 1N sodium hydroxidesolution was added to the reaction mixture to render it alkaline, andthen extraction was performed with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (334 mg, 76%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.73-1.90 (4H, m),2.14-2.22 (2H, m), 2.39-2.48 (1H, m), 2.99-3.06 (2H, m), 3.64 (2H, s),3.77 (2H, s), 7.04 (1H, ddd, J=9.6, 7.8, 1.2 Hz), 7.09 (1H, td, J=7.8,1.2 Hz), 7.15 (1H, td, J=7.8, 2.0 Hz), 7.21-7.28 (1H, m), 7.93 (1H, d,J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 611-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-chlorophenyl)ethanone

After dissolving 252 mg of1-(1-benzylpiperidin-4-yl)-2-(2-chlorophenyl)ethanone in 3 ml of1,2-dichloroethane, 0.1 ml of 1-chloroethyl chloroformate was addedwhile stirring on ice, and the mixture was heated to reflux for 1 hour.The reaction solution was concentrated under reduced pressure, 3 ml ofmethanol was added to the residue, and heating to reflux was continuedfor 30 minutes. The reaction solution was concentrated under reducedpressure, ethyl acetate was added to the residue and the precipitate wasfiltered out to obtain 171 mg of 4-(2-chlorophenylacetyl)piperidinehydrochloride. After then suspending 98 mg of the4-(2-chlorophenylacetyl)piperidine hydrochloride in 3 ml ofdichloromethane, 77 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 114mg of sodium triacetoxyborohydride were added while stirring on ice, andthe stirring was continued overnight at room temperature. A 1N sodiumhydroxide solution was added to the reaction mixture to render italkaline, and then extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (112 mg,78% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.74-1.92 (4H, m),2.14-2.22 (2H, m), 2.42-2.50 (1H, m), 3.00-3.06 (2H, m), 3.64 (2H, s),3.88 (2H, s), 7.16-7.23 (3H, m), 7.34-7.38 (1H, m), 7.93 (1H, d, J=2.8Hz), 8.04 (1H, d, J=2.8 Hz).

Example 621-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2,5-difluorophenyl)ethanone

The title compound (162 mg, 62% yield, 2 steps) was obtained in the samemanner as Example 61 from 215 mg of1-(1-benzylpiperidin-4-yl)-2-(2,5-difluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.74-1.91 (4H, m),2.15-2.24 (2H, m), 2.39-2.48 (1H, m), 3.00-3.06 (2H, m), 3.64 (2H, s),3.75 (2H, d, J=1.2 Hz), 6.85-6.96 (2H, m), 6.96-7.03 (1H, m), 7.93 (1H,d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 631-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(3-methylphenyl)ethanone

The title compound (108 mg, 36% yield, 2 steps) was obtained in the samemanner as Example 61 from 241 mg of1-(1-benzylpiperidin-4-yl)-2-(3-methylphenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.69-1.84 (4H, m),2.10-2.18 (2H, m), 2.33 (3H, s), 2.36-2.45 (1H, m), 2.96-3.04 (2H, m),3.62 (2H, s), 3.69 (2H, s), 6.95-7.00 (2H, m), 7.06 (1H, d, J=7.6 Hz),7.20 (1H, t, J=7.6 Hz), 7.93 (1H, d, J=2.8 Hz), 8.03 (1H, d, J=2.8 Hz).

Example 641-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(3-fluorophenyl)ethanone

The title compound (132 mg, 38% yield, 2 steps) was obtained in the samemanner as Example 61 from 283 mg of1-(1-benzylpiperidin-4-yl)-2-(3-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.70-1.85 (4H, m),2.11-2.20 (2H, m), 2.36-2.46 (1H, m), 2.98-3.05 (2H, m), 3.63 (2H, s),3.73 (2H, s), 6.87-6.98 (3H, m), 7.24-7.32 (1H, m), 7.93 (1H, d, J=2.8Hz), 8.03 (1H, d, J=2.8 Hz).

Example 651-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2,6-difluorophenyl)ethanone

The title compound (43 mg, 54% yield, 2 steps) was obtained in the samemanner as Example 61 from 65 mg of1-(1-benzylpiperidin-4-yl)-2-(2,6-difluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.78-1.94 (4H, m),2.15-2.25 (2H, m), 2.42-2.52 (1H, m), 3.00-3.07 (2H, m), 3.65 (2H, s),3.81 (2H, s), 6.83-6.92 (2H, m), 7.17-7.26 (1H, m), 7.93 (1H, d, J=2.8Hz), 8.04 (1H, d, J=2.8 Hz).

Example 661-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-methylphenyl)ethanone

After suspending 150 mg of 2-(2-methylphenyl)-1-(piperidin-4-yl)ethanonehydrochloride in 3 ml of dichloromethane, 128 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 188 mg of sodiumtriacetoxyborohydride were added while stirring on ice, and the stirringwas continued overnight at room temperature. A 1N sodium hydroxidesolution was added to the reaction mixture to render it alkaline, andthen extraction was performed with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by NH silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (153 mg, 68%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.74-1.84 (4H, m),2.11-2.20 (2H, m), 2.19 (3H, s), 2.37-2.46 (1H, m), 2.98-3.05 (2H, m),3.63 (2H, s), 3.75 (2H, s), 7.04-7.10 (1H, m), 7.12-7.20 (3H, m), 7.93(1H, d, J=2.8 Hz), 8.03 (1H, d, J=2.8 Hz).

Example 672-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-1-(3-chloro-2-thienyl)ethanone

The title compound (226 mg, 75% yield) was obtained in the same manneras Example 1 from 160 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and207 mg of 1-(3-chloro-2-thienyl)-2-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.50 (2H, m), 1.59 (9H, m),1.70-1.78 (2H, m), 1.93-2.07 (1H, m), 2.12-2.20 (2H, m), 2.92 (2H, d,J=6.8 Hz), 2.93-3.00 (2H, m), 3.63 (2H, s), 7.02 (1H, d, J=5.4 Hz), 7.52(1H, d, J=5.4 Hz), 7.92 (1H, d, J=2.4 Hz), 8.04 (1H, d, J=2.4 Hz).

Example 681-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2,3-difluorophenyl)ethanone

The title compound (44 mg, 52% yield) was obtained in the same manner asExample 21 from 45 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 50mg of 2-(2,3-difluorophenyl)-1-(piperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.68-1.90 (4H, m),2.15-2.23 (2H, m), 2.41-2.49 (1H, m), 3.01-3.06 (2H, m), 3.64 (2H, s),3.80 (2H, s), 6.88-6.92 (1H, m), 6.99-7.11 (2H, m), 7.93 (1H, d, J=2.8Hz), 8.40 (1H, d, J=2.8 Hz).

Example 691-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-phenylethanone

The title compound (54 mg, 50% yield) was obtained in the same manner asExample 21 from 64 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 60mg of 2-phenyl-1-(piperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.60-1.65 (1H, m),1.69-1.81 (4H, m), 2.16 (2H, dt, J=11.2, 4 Hz), 2.37-2.45 (1H, m), 3.00(1H, td, J=11.6, 3 Hz), 3.62 (2H, s), 3.73 (2H, s), 7.16-7.19 (2H, m),7.29-7.34 (3H, m), 7.92 (1H, d, J=2.6 Hz), 8.03 (1H, d, J=2.6 Hz).

Example 701-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2,4-difluorophenyl)ethanone

The title compound (33 mg, 57% yield) was obtained in the same manner asExample 21 from 30 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 33mg of 2-(2,4-difluorophenyl)-1-(piperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.74-1.89 (4H, m), 2.18(2H, dt, J=11.6, 2.8 Hz), 2.39-2.47 (1H, m), 3.03 (2H, td, J=12.0, 3.2Hz), 3.64 (2H, s), 3.73 (2H, s), 6.78-6.86 (2H, m), 7.08-7.14 (1H, m),7.94 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 711-(3-tert-Butoxy-2-pyrazinylmethyl)-4-(2-methylphenoxymethyl)piperidin-4-ol

After adding 5 ml of 4N hydrogen chloride/ethyl acetate to 154 mg of1-(tert-butoxycarbonyl)-4-hydroxy-4-(2-methylphenoxymethyl)piperidine,the mixture was stirred for 3 hours at room temperature. The solvent wasdistilled off under reduced pressure to obtain4-hydroxy-4-(2-methylphenoxymethyl)piperidine hydrochloride (123 mg,100% yield). The title compound (28 mg, 46% yield) was then obtained inthe same manner as Example 1 from 29 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 41 mg of the4-hydroxy-4-(2-methylphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.76-1.89 (4H, m), 2.24(3H, s), 2.59 (2H, td, J=11.2, 3.6 Hz), 2.81 (2H, dt, J=12.0, 3.5 Hz),3.70 (2H, s), 3.81 (2H, s), 6.80 (1H, d, J=8.4 Hz), 6.86-6.90 (1H, m),7.13-7.17 (2H, m), 7.93 (1H, d, J=2.6 Hz), 8.05 (1H, d, J=2.6 Hz).

Example 721-(3-tert-Butoxy-2-pyrazinylmethyl)-4-(2-fluorophenoxymethyl)piperidin-4-ol

4-(2-Fluorophenoxymethyl)-4-hydroxypiperidine hydrochloride (98 mg, 100%yield) was obtained in the same manner as Example 71 from 103 mg of1-(tert-butoxycarbonyl)-4-(2-fluorophenoxymethyl)-4-hydroxypiperidine.

The title compound (27 mg, 45% yield) was then obtained from 25 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 40 mg of4-(2-fluorophenoxymethyl)-4-hydroxypiperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.76-1.87 (4H, m), 2.58(2H, td, J=10.6, 4.8 Hz), 2.80 (2H, dt, J=11.6, 3.6 Hz), 3.69 (2H, s),3.86 (2H, s), 6.88-6.98 (2H, m), 7.00-7.10 (2H, m), 7.93 (1H, d, J=2.6Hz), 8.05 (1H, d, J=2.6 Hz).

Example 731-(3-tert-Butoxy-2-pyrazinylmethyl)-4-(2-methyl-5-phenylpyrrol-1-yl)methyl-piperidin-4-ol

The title compound (43 mg, 76% yield) was obtained in the same manner asExample 6 from 23 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 35 mgof 4-hydroxy-4-(2-phenyl-5-methylpyrrol-1-yl)methyl-piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.20-1.60 (6H, m), 1.55 (9H, s),2.20-2.29 (2H, m), 2.37 (3H, s), 2.53-2.65 (2H, m), 3.53 (2H, s), 5.90(1H, d, J=3.6 Hz), 6.10 (1H, d, J=3.6 Hz), 7.23-7.27 (1H, m), 7.30-7.37(4H, m), 7.88 (1H, d, J=2.6 Hz), 8.00 (1H, d, J=2.6 Hz).

Example 74N-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-4-hydroxypiperidin-4-yl]methyl-2-fluorobenzamide

The title compound (18 mg, 52% yield) was obtained in the same manner asExample 6 from 23 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 21 mgof 2-fluoro-N-(4-hydroxypiperidin-4-yl)methyl-benzamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.64-1.69 (2H, m),1.72-1.80 (2H, m), 2.55 (2H, td, J=11.2, 3.2 Hz), 2.72-2.78 (2H, m),3.50 (2H, d, J=6.0 Hz), 3.68 (2H, s), 6.62 (1H, t, J=6.0 Hz), 7.41-7.46(2H, m), 7.48-7.53 (1H, m), 7.77-7.80 (2H, m), 7.92 (1H, d, J=2.6 Hz),8.03 (1H, d, J=2.6 Hz).

Example 75N-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-4-hydroxypiperidin-4-yl]methyl-2-fluoro-N-(2-fluorobenzoyl)benzamide

The title compound (7 mg, 32% yield) was obtained in the same manner asExample 6 from 9 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 15 mgof2-fluoro-N-(2-fluorobenzoyl)-N-(4-hydroxypiperidin-4-yl)methyl-benzamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.92-2.00 (2H, m), 2.39(2H, d, J=10.0 Hz), 2.57 (2H, t, J=10.2 Hz), 2.80-2.86 (2H, m), 3.67(2H, s), 4.08-4.09 (2H, m), 7.07-7.17 (2H, m), 7.20-7.27 (2H, m),7.42-7.53 (2H, m), 7.90-7.97 (2H, m), 8.00-8.08 (2H, m).

Example 76 Ethyl1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-phenylethyl)piperidine-4-carboxylate

The title compound (336 mg, 57% yield) was obtained in the same manneras Example 1 from 405 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and446 mg of 4-(ethoxycarbonyl)-4-(2-phenylethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.28 (3H, t, J=7.0 Hz),1.60-1.68 (2H, m), 1.74-1.83 (2H, m), 2.14-2.27 (4H, m), 2.48-2.53 (2H,m), 2.80-2.87 (2H, m), 3.60 (2H, s), 4.18 (2H, q, J=7.0 Hz), 7.12-7.19(2H, m), 7.24-7.29 (3H, m), 7.91 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8Hz).

Example 771-(3-tert-Butoxy-2-pyrazinylmethyl)-4-[(2-fluorophenyl)ethynyl]piperidin-4-ol

The title compound (102 mg, 69% yield) was obtained in the same manneras Example 1 from 90 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 98mg of 4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.94-2.05 (2H, m),2.05-2.15 (2H, m), 2.59-2.67 (2H, m), 2.82-2.89 (2H, m), 3.70 (2H, s),7.03-7.11 (2H, m), 7.27-7.32 (1H, m), 7.40 (1H, td, J=7.6, 1.6 Hz), 7.93(1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 781-(3-tert-Butoxy-2-pyrazinylmethyl)-4-[(2-methylphenyl)ethynyl]piperidin-4-ol

4-Hydroxy-4-[(2-methylphenyl)ethynyl]piperidine hydrochloride (1.1 g,100% yield) was obtained in the same manner as Example 71 from 1.22 g of1-(tert-butoxycarbonyl)-4-hydroxy-4-[(2-methylphenyl)ethynyl]piperidine.

The title compound (103 mg, 76% yield) was then obtained from 84 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 90 mg of the4-hydroxy-4-[(2-methylphenyl)ethynyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.95-2.01 (2H, m),2.04-2.10 (2H, m), 2.39 (3H, s), 2.56-2.66 (2H, m), 2.85-2.90 (2H, m),3.70 (2H, s), 7.13 (1H, td, J=7.2, 2.0 Hz), 7.16-7.24 (2H, m), 7.38 (1H,d, J=7.2 Hz), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 791-(3-tert-Butoxy-2-pyrazinylmethyl)-4-(2-phenylethyl)piperidine-4-methanol

The title compound (62 mg, 23% yield) was obtained in the same manner asExample 3 from 306 mg of ethyl1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-phenylethyl)-4-piperidinecarboxylate.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.59 (2H, m), 1.60 (9H, s),1.64-1.76 (4H, m), 2.49-2.63 (6H, m), 3.55 (2H, s), 3.65 (2H, s),7.16-7.21 (3H, m), 7.26-7.30 (2H, m), 7.92 (1H, d, J=2.4 Hz), 8.04 (1H,d, J=2.4 Hz).

Example 801-(3-tert-Butoxy-2-pyrazinylmethyl)-4-[2-(2-fluorophenyl)ethyl]piperidin-4-ol

The title compound (19 mg, 18% yield) was obtained in the same manner asExample 1 from 54 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 54 mgof 4-[2-(2-fluorophenyl)ethyl]-4-hydroxypiperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.73-1.84 (4H, m),2.45-2.54 (4H, m), 2.72-2.80 (4H, m), 3.68 (2H, s), 6.99 (1H, ddd,J=9.6, 8.0, 0.8 Hz), 7.05 (1H, td, J=7.4, 1.2 Hz), 7.13-7.21 (2H, m),7.92 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 811-(3-tert-Butoxy-2-pyrazinylmethyl)-4-(2-fluorophenoxymethyl)piperidine-4-carbonitrile

The title compound (55 mg, 33% yield) was obtained in the same manner asExample 1 from 98 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 113mg of 4-cyano-4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.86 (2H, td, J=13.2, 3.2Hz), 2.10 (2H, dd, J=13.2, 2.2 Hz), 2.54 (2H, td, J=12.2, 2.2 Hz),3.03-3.09 (2H, m), 3.72 (2H, s), 4.03 (2H, s), 6.93-7.01 (2H, m),7.03-7.11 (2H, m), 7.94 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 821-(3-tert-Butoxy-2-pyrazinylmethyl)-4-(2-methylphenoxymethyl)piperidine-4-carbonitrile

The title compound (47 mg, 24% yield) was obtained in the same manner asExample 1 from 115 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 131mg of 4-cyano-4-(2-methylphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.63 (9H, s), 1.86 (2H, td, J=13.2, 3.5Hz), 2.10-2.15 (2H, m), 2.29 (3H, s), 2.44-2.60 (2H, m), 3.05-3.10 (2H,m), 3.74 (2H, s), 3.97 (2H, s), 6.74-6.78 (1H, m), 6.88-6.94 (1H, m),7.14-7.18 (2H, m), 7.96 (1H, d, J=2.6 Hz), 8.07 (1H, d, J=2.6 Hz).

Example 831-(3-tert-Butoxy-2-pyrazinylmethyl)-4-[2-(2-methylphenyl)ethyl]piperidin-4-ol

The title compound (138 mg, 71% yield) was obtained in the same manneras Example 1 from 119 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and130 mg of 4-hydroxy-4-[2-(2-methylphenyl)ethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.60-1.72 (4H, m), 1.84(2H, td, J=13.6, 4.4 Hz), 2.30 (3H, s), 2.51 (2H, td, J=11.4, 2.4 Hz),2.66-2.71 (2H, m), 2.75-2.82 (2H, m), 3.68 (2H, s), 7.07-7.15 (4H, m),7.92 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 84 2-tert-Butoxy-3-[4-fluoro-4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine

4-Fluoro-4-(2-fluorophenoxymethyl)piperidine hydrochloride (119 mg, 100%yield) was obtained in the same manner as Example 71 from 150 mg of1-(tert-butoxycarbonyl)-4-fluoro-4-(2-fluorophenoxymethyl)piperidine.

The title compound (18 mg, 20% yield) was then obtained from 53 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 60 mg of the4-fluoro-4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.86-1.95 (2H, m),1.98-2.06 (2H, m), 2.49-2.56 (2H, m), 2.85-2.91 (2H, m), 3.69 (2H, s),4.02 (2H, d, J=18.8 Hz), 6.89-6.96 (1H, m), 6.98 (1H, dd, J=8.0, 1.6Hz), 7.00-7.10 (2H, m), 7.93 (1H, d, J=2.6 Hz), 8.05 (1H, d, J=2.6 Hz).

Example 852-tert-Butoxy-3-[4-(2-fluorophenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-pyrazine

The title compound (40 mg, 40% yield) was obtained in the same manner asExample 1 from 47 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 74 mgof 4-(2-fluorophenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidinehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.69-1.87 (6H, m),2.51-2.65 (6H, m), 3.66 (2H, s), 3.89 (2H, s), 6.84-7.26 (8H, m),7.90-7.93 (1H, m), 8.03-8.05 (1H, m).

Example 862-tert-Butoxy-3-[4-[2-(2-fluorophenyl)ethyl]-4-(2-methylphenoxymethyl)piperidino]methyl-pyrazine

The title compound (21 mg, 18% yield) was obtained in the same manner asExample 1 from 56 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 87 mgof 4-[2-(2-fluorophenyl)ethyl]-4-(2-methylphenoxymethyl)piperidinehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.67-1.87 (6H, m), 2.25(3H, s), 2.55-2.63 (6H, m), 3.66 (2H, s), 3.80 (2H, s), 6.74-6.91 (2H,m), 6.95-7.04 (2H, m), 7.05-7.22 (4H, m), 7.92 (1H, d, J=2.6 Hz), 8.04(1H, d, J=2.6 Hz).

Example 877-(3-tert-Butoxy-2-pyrazinylmethyl)-2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane2-(2-Fluorophenoxy)-7-azaspiro[3.5]nonane hydrochloride (176 mg) wasobtained in the same manner as Example 71 from 163 mg of7-(tert-butoxycarbonyl)-2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane.

The title compound (33 mg, 38% yield) was then obtained from 51 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 59 mg of2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.57 (9H, s), 1.66-1.72 (4H, m),1.94-2.01 (2H, m), 2.35-2.40 (2H, m), 2.45 (2H, brs), 2.51 (2H, brs),3.60 (2H, s), 4.68 (1H, quintet, J=6.8 Hz), 6.79 (1H, td, J=8.2, 1.6Hz), 6.86 (1H, tdd, J=7.8, 4.4, 1.6 Hz), 6.99-7.03 (1H, m), 7.06 (1H,ddd, J=11.4, 7.8, 1.6 Hz), 7.92 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8Hz).

Example 882-tert-Butoxy-3-[4-[2-(2-methylphenyl)ethyl]azepan-1-yl]methyl-pyrazine

The title compound (109 mg, 72% yield) was obtained in the same manneras Example 21 from 105 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and84 mg of 4-[2-(2-methylphenyl)ethyl]azepane.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.52 (4H, m), 1.60 (9H, s),1.61-1.67 (2H, m), 1.71-1.84 (3H, m), 2.29 (3H, s), 2.55-2.59 (2H, m),2.68 (1H, ddd, J=13.0, 9.6, 3.0 Hz), 2.76-2.80 (2H, m), 2.88 (1H, ddd,J=13.0, 7.2, 3.0 Hz), 3.75-3.76 (2H, m), 7.06-7.14 (4H, m), 7.91 (1H, d,J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 894-tert-Butoxy-5-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrimidine

After dissolving 976 mg of ethyl 4-tert-butoxypyrimidine-5-carboxylatein 15 ml of toluene, the solution was cooled to −78° C. 3.2 ml ofdiisobutylaluminium hydride (1.5 M, toluene solution) was added dropwisewhile stirring, and then after 30 minutes, an aqueous solution ofpotassium sodium (+)-tartrate was added and the mixture was stirred atroom temperature. Water was added to the reaction solution andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure to obtain 0.85 g of crude4-tert-butoxypyrimidine-5-carboxaldehyde.

This was dissolved in 5 ml of dichloromethane, and then 200 mg of4-(2-fluorophenoxymethyl)piperidine hydrochloride and 259 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. Aqueous sodium bicarbonate solution was added tothe reaction mixture and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (167 mg, 55% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.49 (2H, m), 1.63 (9H, s),1.75-1.92 (3H, m), 2.07-2.15 (2H, m), 2.89-2.96 (2H, m), 3.45 (2H, s),3.86 (2H, d, J=6.0 Hz), 6.85-6.91 (1H, m), 6.95 (1H, dt, J=8.0, 1.6 Hz),7.01-7.10 (2H, m), 8.41 (1H, s), 8.61 (1H, s).

Example 902-tert-Butoxy-3-[4-[2-(2-fluorophenoxy)ethyl]piperidino]methyl-pyrazine

The title compound (244 mg, 81% yield) was obtained in the same manneras Example 1 from 161 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and202 mg of 4-[2-(2-fluorophenoxy)ethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.47 (2H, m), 1.50-1.66 (1H, m),1.60 (9H, s), 1.67-1.80 (4H, m), 2.08-2.17 (2H, m), 2.94-3.03 (2H, m),3.63 (2H, s), 4.06 (2H, t, J=6.4 Hz), 6.84-6.91 (1H, m), 6.95 (1H, td,J=8.2, 1.6 Hz), 7.01-7.10 (2H, m), 7.92 (1H, d, J=2.8 Hz), 8.04 (1H, d,J=2.8 Hz).

Example 912-tert-Butoxy-3-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine

After adding 139 mg of (Z)-2-tert-butoxy-3-(2-methoxyvinyl)pyrazine and196 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride in 5 ml ofdichloromethane, 213 mg of sodium triacetoxyborohydride was added andthe mixture was stirred overnight at room temperature. Aqueous sodiumcarbonate solution was added to the reaction mixture and extraction wasperformed with ethyl acetate. The organic layer was washed with waterand saturated brine in that order and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain the title compound (26 mg, 10% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.48 (2H, m), 1.60 (9H, s),1.82-1.93 (3H, m), 2.09-2.17 (2H, m), 2.74-2.80 (2H, m), 2.96-3.01 (2H,m), 3.03-3.10 (2H, m), 3.87 (2H, d, J=6.4 Hz), 6.85-6.91 (1H, m), 6.95(1H, dt, J=8.0, 1.6 Hz), 7.01-7.10 (2H, m), 7.89 (1H, d, J=2.8 Hz), 7.94(1H, d, J=2.8 Hz).

Example 922-tert-Butoxy-3-[4-(2-fluorobenzyloxymethyl)piperidino]methyl-pyrazine

The title compound (259 mg, 95% yield) was obtained in the same manneras Example 1 from 152 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and183 mg of 4-(2-fluorobenzyloxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.30-1.42 (2H, m), 1.55-1.78 (3H, m),1.60 (9H, s), 2.06-2.16 (2H, m), 2.97-3.04 (2H, m), 3.35 (2H, d, J=6.8Hz), 3.64 (2H, s), 4.57 (2H, s), 7.03 (1H, ddd, J=9.6, 7.8, 1.2 Hz),7.13 (1H, td, J=7.8, 1.2 Hz), 7.22-7.31 (1H, m), 7.42 (1H, td, J=7.8,1.2 Hz), 7.92 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 93(E)-2-tert-Butoxy-3-[4-[2-(3-chloro-2-thienyl)vinyl]piperidino]methyl-pyrazine

The title compound (259 mg, 80% yield) was obtained in the same manneras Example 1 from 175 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and211 mg of (E)-4-[2-(3-chloro-2-thienyl)vinyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.53-1.66 (2H, m), 1.61 (9H, s),1.70-1.78 (2H, m), 2.08-2.22 (3H, m), 2.99-3.05 (2H, m), 3.65 (2H, s),6.04 (1H, dd, J=16.0, 7.2 Hz), 6.56 (1H, ddd, J=16.0, 1.2, 0.8 Hz), 6.83(1H, d, J=5.4 Hz), 7.05 (1H, dd, J=5.4, 0.8 Hz), 7.93 (1H, d, J=2.8 Hz),8.05 (1H, d, J=2.8 Hz).

Example 942-tert-Butoxy-3-[4-[2-(3-fluoro-2-thienyl)ethyl]piperidino]methyl-pyrazine

The title compound (69 mg, 35% yield) was obtained in the same manner asExample 21 from 113 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 112mg of 4-[2-(3-fluoro-2-thienyl)ethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.40 (3H, m), 1.52-1.73 (4H, m),1.59 (9H, s), 2.03-2.12 (2H, m), 2.70-2.76 (2H, m), 2.94-3.01 (2H, m),3.62 (2H, s), 6.72 (1H, dd, J=5.6, 0.8 Hz), 6.96 (1H, dd, J=5.6, 4.0Hz), 7.91 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 95(E)-2-tert-Butoxy-3-[4-[2-(3-fluoro-2-thienyl)vinyl]piperidino]methyl-pyrazine

The title compound (242 mg, 94% yield) was obtained in the same manneras Example 1 from 147 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and169 mg of (E)-4-[2-(3-fluoro-2-thienyl)vinyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.50-1.64 (2H, m), 1.60 (9H, s),1.69-1.76 (2H, m), 2.04-2.21 (3H, m), 2.98-3.05 (2H, m), 3.64 (2H, s),5.93 (1H, dd, J=16.0, 6.8 Hz), 6.44 (1H, dd, J=16.0, 0.8 Hz), 6.72 (1H,dd, J=5.6, 0.8 Hz), 6.94 (1H, dd, J=5.6, 4.0 Hz), 7.93 (1H, d, J=2.8Hz), 8.05 (1H, d, J=2.8 Hz).

Example 962-tert-Butoxy-3-[4-[1-(2-fluorophenoxy)ethyl]piperidino]methyl-pyrazine

The title compound (400 mg, 96% yield) was obtained in the same manneras Example 21 from 231 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and239 mg of 4-[1-(2-fluorophenoxy)ethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.26 (3H, d, J=6.4 Hz), 1.42-1.58 (2H,m), 1.60 (9H, s), 1.60-1.77 (2H, m), 1.88-1.96 (1H, m), 2.07-2.16 (2H,m), 3.01-3.09 (2H, m), 3.64 (2H, s), 4.09-4.16 (1H, m), 6.85-6.91 (1H,m), 6.95 (1H, td, J=8.4, 2.0 Hz), 7.00-7.09 (2H, m), 7.92 (1H, d, J=2.8Hz), 8.04 (1H, d, J=2.8 Hz).

Example 972-tert-Butoxy-6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine

After dissolving 262 mg of 2-tert-butoxy-6-vinylpyrazine and 401 mg of4-(2-fluorophenoxymethyl)piperidine [CAS No. 63608-34-4] in 3 ml ofethanol, the mixture was stirred for 2 days at 80° C. The reactionsolution was concentrated under reduced pressure, and the residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (67 mg, 12% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.48 (2H, m), 1.59 (9H, s),1.82-1.94 (3H, m), 2.04-2.13 (2H, m), 2.73-2.79 (2H, m), 2.85-2.91 (2H,m), 3.00-3.06 (2H, m), 3.87 (2H, d, J=6.4 Hz), 6.85-6.91 (1H, m), 6.95(1H, dt, J=8.0, 1.6 Hz), 7.02-7.10 (2H, m), 7.91 (1H, s), 7.93 (1H, s).

Example 982-tert-Butoxy-6-[2-[4-(2-methoxyphenoxymethyl)piperidino]ethyl]pyrazine

The title compound (305 mg, 33% yield) was obtained in the same manneras Example 97 from 418 mg of 2-tert-butoxy-6-vinylpyrazine and 510 mg of4-(2-methoxyphenoxymethyl)piperidine [CAS No. 63608-36-6].

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.46 (2H, m), 1.59 (9H, s),1.88-1.99 (3H, m), 2.04-2.12 (2H, m), 2.73-2.78 (2H, m), 2.85-2.91 (2H,m), 2.99-3.06 (2H, m), 3.86 (2H, d, J=6.0 Hz), 3.86 (3H, s), 6.87-9.65(4H, m), 7.91 (1H, s), 7.93 (1H, s).

Example 992-tert-Butoxy-6-[2-[4-(2,3-difluorophenoxymethyl)piperidino]ethyl]pyrazine

The title compound (172 mg, 19% yield) was obtained in the same manneras Example 97 from 384 mg of 2-tert-butoxy-6-vinylpyrazine and 490 mg of4-(2,3-difluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.48 (2H, m), 1.60 (9H, s),1.82-1.94 (3H, m), 2.05-2.13 (2H, m), 2.74-2.80 (2H, m), 2.85-2.91 (2H,m), 3.00-3.07 (2H, m), 3.87 (2H, d, J=6.4 Hz), 6.69-6.80 (2H, m),6.93-7.00 (1H, m), 7.91 (1H, s), 7.94 (1H, s).

Example 1002-tert-Butoxy-6-[2-[4-[2-(2-fluorophenyl)ethyl]piperidino]ethyl]pyrazine

The title compound (309 mg, 47% yield) was obtained in the same manneras Example 97 from 311 mg of 2-tert-butoxy-6-vinylpyrazine and 362 mg of4-[2-(2-fluorophenyl)ethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.37 (3H, m), 1.53-1.62 (2H, m),1.59 (9H, s), 1.74-1.82 (2H, m), 1.96-2.05 (2H, m), 2.63-2.69 (2H, m),2.70-2.76 (2H, m), 2.84-2.90 (2H, m), 2.95-3.01 (2H, m), 6.97-7.03 (1H,m), 7.05 (1H, dt, J=7.2, 1.2 Hz), 7.13-7.21 (2H, m), 7.90 (1H, s), 7.93(1H, s).

Example 1012-tert-Butoxy-6-[2-[4-[(2-fluorophenyl)ethynyl]piperidino]ethyl]pyrazine

The title compound (59 mg, 10% yield) was obtained in the same manner asExample 97 from 286 mg of 2-tert-butoxy-6-vinylpyrazine and 326 mg of4-[(2-fluorophenyl)ethynyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.74-1.85 (2H, m),1.92-2.01 (2H, m), 2.28-2.40 (2H, m), 2.70 (1H, br s), 2.74-2.91 (6H,m), 7.02-7.09 (2H, m), 7.22-7.28 (1H, m), 7.39 (1H, dt, J=7.2, 1.6 Hz),7.91 (1H, s), 7.94 (1H, s).

Example 1022-tert-Butoxy-6-[2-[3-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine

The title compound (160 mg, 24% yield) was obtained in the same manneras Example 97 from 300 mg of 2-tert-butoxy-6-vinylpyrazine and 352 mg of3-(2-fluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.12-1.23 (1H, m), 1.59 (9H, s),1.58-1.68 (1H, m), 1.69-1.85 (2H, m), 1.98-2.22 (3H, m), 2.70-2.84 (5H,m), 3.08 (1H, d, J=9.6 Hz), 3.88 (1H, dd, J=9.6, 7.2 Hz), 3.92 (1H, dd,J=5.6, 9.6 Hz), 6.85-6.92 (1H, m), 6.94 (1H, dt, J=8.0, 1.6 Hz),7.01-7.10 (2H, m), 7.89 (1H, s), 7.92 (1H, s).

Example 1032-tert-Butoxy-6-[2-[4-(2,6-difluorophenoxymethyl)piperidino]ethyl]pyrazine

The title compound (316 mg, 39% yield) was obtained in the same manneras Example 97 from 363 mg of 2-tert-butoxy-6-vinylpyrazine and 463 mg of4-(2,6-difluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.45 (2H, m), 1.59 (9H, s),1.76-1.93 (3H, m), 2.04-2.12 (2H, m), 2.72-2.78 (2H, m), 2.85-2.91 (2H,m), 2.99-3.06 (2H, m), 3.97 (2H, d, J=6.0 Hz), 6.83-6.98 (3H, m), 7.91(1H, s), 7.93 (1H, s).

Example 1042-tert-Butoxy-6-[2-[4-(2,5-difluorophenoxymethyl)piperidino]ethyl]pyrazine

The title compound (236 mg, 26% yield) was obtained in the same manneras Example 97 from 402 mg of 2-tert-butoxy-6-vinylpyrazine and 504 mg of4-(2,5-difluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.49 (2H, m), 1.59 (9H, s),1.83-1.94 (3H, m), 2.04-2.16 (2H, m), 2.72-2.81 (2H, m), 2.84-2.92 (2H,m), 3.00-3.08 (2H, m), 3.83 (2H, d, J=6.0 Hz), 6.52-6.59 (1H, m),6.64-6.70 (1H, m), 6.96-7.04 (1H, m), 7.90 (1H, s), 7.93 (1H, s).

Example 1052-[1-[2-(6-tert-Butoxypyrazin-2-yl)ethyl]piperidin-4-yl]-1-(2-fluorophenyl)ethanone

The title compound (93 mg, 14% yield) was obtained in the same manner asExample 97 from 295 mg of 2-tert-butoxy-6-vinylpyrazine and 463 mg of1-(2-fluorophenyl)-2-(piperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.49 (2H, m), 1.58 (9H, s),1.75-1.83 (2H, m), 1.94-2.18 (3H, m), 2.67-3.04 (8H, m), 7.24-7.28 (1H,m), 7.40-7.48 (1H, m), 7.59-7.64 (1H, m), 7.70-7.74 (1H, m), 7.90 (1H,s), 7.92 (1H, s).

Example 1061-[2-(6-tert-Butoxypyrazin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-ol

The title compound (274 mg, 31% yield) was obtained in the same manneras Example 97 from 398 mg of 2-tert-butoxy-6-vinylpyrazine and 503 mg of4-(2-fluorophenoxymethyl)-4-hydroxypiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.71-1.87 (4H, m), 2.25(1H, br s), 2.48-2.57 (2H, m), 2.74-2.84 (4H, m), 2.88-2.92 (2H, m),3.87 (2H, s), 6.89-7.00 (2H, m), 7.03-7.12 (2H, m), 7.91 (1H, s), 7.94(1H, s).

Example 1077-[2-(6-tert-Butoxypyrazin-2-yl)ethyl]-2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane

The title compound (7 mg, 8% yield) was obtained in the same manner asExample 97 from 47 mg of 2-tert-butoxy-6-vinylpyrazine and 52 mg of2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.65-1.71 (4H, m), 1.99(2H, dd, J=13.2, 6.4 Hz), 2.36-2.50 (6H, m), 2.71 (2H, dd, J=9.2, 6.8Hz), 2.56 (2H, dd, J=9.2, 6.8 Hz), 4.69 (1H, quintet, J=6.8 Hz), 6.79(1H, td, J=8.4, 7.0 Hz), 6.87 (1H, tdd, J=7.6, 4.4, 1.6 Hz), 7.01 (1H,t, J=7.8 Hz), 7.07 (1H, ddd, J=11.6, 8.0, 1.6 Hz), 7.90 (1H, s), 7.92(1H, s).

Example 1081-[2-(6-tert-Butoxypyrazin-2-yl)ethyl]-4-[(2-fluorophenyl)ethynyl]piperidin-4-ol

The title compound (146 mg, 67% yield) was obtained in the same manneras Example 97 from 110 mg of 2-tert-butoxy-6-vinylpyrazine and 121 mg of4-(2-fluorophenyl)ethynyl-4-hydroxypiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.95 (2H, ddd, J=13.0,5.6, 3.6 Hz), 2.04-2.12 (2H, m), 2.56 (2H, t, J=9.4 Hz), 2.79-2.91 (6H,m), 7.04-7.12 (2H, m), 7.26-7.33 (1H, m), 7.38-7.44 (1H, m), 7.91 (1H,s), 7.93 (1H, s).

Example 1092-tert-Butoxy-4-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrimidine

After dissolving 221 mg of 2-tert-butoxy-4-vinylpyrimidine and 200 mg of4-(2-fluorophenoxymethyl)piperidine hydrochloride in 5 ml of ethanol,123 mg of anhydrous potassium carbonate was added and the mixture washeated to reflux for 50 minutes. Ethyl acetate was added to the reactionmixture, the insoluble portion was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (293 mg, 93% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.33-1.48 (2H, m), 1.63 (9H, s),1.81-1.93 (3H, m), 2.04-2.12 (2H, m), 2.74-2.80 (2H, m), 2.84-2.91 (2H,m), 2.98-3.04 (2H, m), 3.86 (2H, d, J=6.0 Hz), 6.75 (1H, d, J=4.8 Hz),6.85-6.91 (1H, m), 6.94 (1H, dt, J=8.0, 1.6 Hz), 7.01-7.10 (2H, m), 8.32(1H, d, J=4.8 Hz).

Example 1104-tert-Butoxy-2-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrimidine

The title compound (282 mg, 89% yield) was obtained in the same manneras Example 109 from 221 mg of 4-tert-butoxy-2-vinylpyrimidine and 200 mgof 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.47 (2H, m), 1.61 (9H, s),1.82-1.93 (3H, m), 2.06-2.14 (2H, m), 2.86-2.92 (2H, m), 3.01-3.08 (4H,m), 3.86 (2H, d, J=6.0 Hz), 6.42 (1H, d, J=6.0 Hz), 6.84-6.91 (1H, m),6.95 (1H, dt, J=8.0, 1.6 Hz), 7.01-7.10 (2H, m), 8.27 (1H, d, J=6.0 Hz).

Example 1111-[2-(6-tert-Butoxypyridin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-ol

After dissolving 400 mg of 2-tert-butoxy-6-vinylpyridine and 601 mg of4-(2-fluorophenoxymethyl)-4-hydroxypiperidine hydrochloride in 5 ml ofN,N-dimethylformamide, 0.44 ml of N,N-diisopropylethylamine was addedand the mixture was stirred for 24 hours at 100° C. Water was added tothe reaction solution and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (18 mg, 2% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.73-1.88 (4H, m),2.49-2.58 (2H, m), 2.76-2.93 (6H, m), 3.88 (2H, s), 6.46 (1H, d, J=8.0Hz), 6.68 (1H, d, J=7.6 Hz), 6.89-7.00 (2H, m), 7.03-7.12 (2H, m), 7.41(1H, dd, J=8.0, 7.6 Hz).

Example 1122-tert-Butoxy-6-[2-[4-(2,4-difluorophenoxymethyl)piperidino]ethyl]pyrazine

The title compound (280 mg, 31% yield) was obtained in the same manneras Example 97 from 405 mg of 2-tert-butoxy-6-vinylpyrazine and 508 mg of4-(2,4-difluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.47 (2H, m), 1.59 (9H, s),1.80-1.91 (3H, m), 2.04-2.12 (2H, m), 2.73-2.79 (2H, m), 2.85-2.91 (2H,m), 3.00-3.06 (2H, m), 3.83 (2H, d, J=6.0 Hz), 6.74-6.80 (1H, m),6.82-6.93 (2H, m), 7.91 (1H, s), 7.93 (1H, s).

Example 113(E)-2-tert-Butoxy-6-[2-[4-[2-(2-fluorophenyl)vinyl]piperidino]ethyl]pyrazine

The title compound (13 mg, 5% yield) was obtained in the same manner asExample 109 from 180 mg of 2-tert-butoxy-6-vinylpyrazine and 160 mg of(E)-4-[2-(2-fluorophenyl)vinyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.51-1.64 (2H, m), 1.60 (9H, s),1.77-1.85 (2H, m), 2.08-2.24 (3H, m), 2.74-2.80 (2H, m), 2.86-2.92 (2H,m), 3.00-3.07 (2H, m), 6.24 (1H, dd, J=16.0, 7.2 Hz), 6.55 (1H, d,J=16.0 Hz), 7.01 (1H, ddd, J=10.8, 8.4, 1.2 Hz), 7.06 (1H, dt, J=7.6,1.2 Hz), 7.15-7.20 (1H, m), 7.44 (1H, dt, J=7.6, 1.6 Hz), 7.91 (1H, s),7.94 (1H, s).

Example 1142-tert-Butoxy-6-[2-[4-(2-chlorophenoxymethyl)piperidino]ethyl]pyrazine

After adding 1.16 g of 2-tert-butoxy-6-vinylpyrazine, 860 mg of4-(2-chlorophenoxymethyl)piperidine hydrochloride and 0.43 g ofanhydrous potassium carbonate to 10 ml of N,N-dimethylformamide, themixture was stirred for 2 days at 100° C. Ice water was added to thereaction mixture and extraction was performed with ethyl acetate. Theorganic layer was washed with water and saturated brine in that orderand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate) toobtain the title compound (145 mg, 11% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.50 (2H, m), 1.59 (9H, s),1.84-1.96 (3H, m), 2.06-2.14 (2H, m), 2.74-2.80 (2H, m), 2.86-2.91 (2H,m), 3.01-3.07 (2H, m), 3.86 (2H, d, J=6.0 Hz), 6.88 (1H, dt, J=7.6, 1.2Hz), 6.90 (1H, dt, J=8.0, 1.2 Hz), 7.20 (1H, ddd, J=8.0, 7.6, 1.6 Hz),7.35 (1H, dd, J=7.6, 1.6 Hz), 7.91 (1H, d, J=0.4 Hz), 7.93 (1H, d, J=0.4Hz).

Example 1152-tert-Butoxy-6-[2-[4-(2-methylphenoxymethyl)piperidino]ethyl]pyrazine

The title compound (152 mg, 21% yield) was obtained in the same manneras Example 114 from 516 mg of 2-tert-butoxy-6-vinylpyrazine and 450 mgof 4-(2-methylphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.52 (2H, m), 1.59 (9H, s),1.80-1.92 (3H, m), 2.06-2.14 (2H, m), 2.23 (3H, s), 2.74-2.80 (2H, m),2.86-2.92 (2H, m), 3.01-3.07 (2H, m), 3.81 (2H, d, J=6.0 Hz), 6.80 (1H,d, J=8.0 Hz), 6.85 (1H, dt, J=7.6, 0.8 Hz), 7.11-7.17 (2H, m), 7.91 (1H,s), 7.94 (1H, s).

Example 1162-tert-Butoxy-6-[2-[4-(3-fluorophenoxymethyl)piperidino]ethyl]pyrazine

The title compound (304 mg, 30% yield) was obtained in the same manneras Example 97 from 470 mg of 2-tert-butoxy-6-vinylpyrazine and 543 mg of4-(3-fluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.48 (2H, m), 1.59 (9H, s),1.76-1.89 (3H, m), 2.04-2.12 (2H, m), 2.73-2.79 (2H, m), 2.85-2.92 (2H,m), 3.00-3.07 (2H, m), 3.79 (2H, d, J=6.0 Hz), 6.58-6.69 (3H, m), 7.21(1H, dt, J=8.4, 6.8 Hz), 7.91 (1H, s), 7.93 (1H, s).

Example 1176-[2-[3-(2-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

After dissolving 160 mg of2-tert-butoxy-6-[2-[3-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazinein 2 ml of ethyl acetate, 2 ml of 4N hydrogen chloride/ethyl acetate wasadded, and the mixture was allowed to stand at room temperature for 30minutes. Aqueous sodium bicarbonate solution was added to the reactionsolution and extraction was performed with dichloromethane. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was dissolved in ethyl acetate, activecarbon was added, and the mixture was filtered. The filtrate wasconcentrated under reduced pressure to obtain the title compound (108mg, 79% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.27-1.40 (1H, m), 1.71-1.89 (3H, m),2.15-2.36 (3H, m), 2.62-2.67 (2H, m), 2.74-2.79 (2H, m), 2.87-2.94 (1H,m), 3.08-3.15 (1H, m), 3.91 (1H, dd, J=9.6, 7.2 Hz), 4.01 (1H, dd,J=5.2, 9.6 Hz), 6.86-6.92 (1H, m), 6.97-7.08 (3H, m), 7.11 (1H, s), 7.99(1H, s).

Example 1186-[2-[4-Hydroxy-4-(2-fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

After dissolving 274 mg of1-[2-(6-tert-butoxypyrazin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-olin 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was allowed to stand at room temperature for 2hours. Aqueous sodium bicarbonate solution was added to the reactionsolution and extraction was performed with dichloromethane. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. Diethyl ether was added to the residue and the mixturewas filtered to obtain the title compound (186 mg, 79% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.77-1.87 (2H, m), 1.88-1.95 (2H, m),2.54-2.68 (4H, m), 2.79-2.84 (2H, m), 2.85-2.92 (2H, m), 3.93 (2H, s),6.91-7.01 (2H, m), 7.04-7.12 (2H, m), 7.16 (1H, s), 8.01 (1H, s).

Example 1196-[2-[2-(2-Fluorophenoxy)-7-azaspiro[3.5]non-7-yl]ethyl]-1H-pyrazin-2-one

The title compound (6 mg, 99% yield) was obtained in the same manner asExample 118 from 7 mg of7-[2-(6-tert-butoxypyrazin-2-yl)ethyl]-2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.75-1.78 (4H, m), 2.00-2.10 (2H, m),2.39-2.65 (8H, m), 2.69-2.74 (2H, m), 4.71 (1H, quintet, J=6.8 Hz), 6.79(1H, td, J=8.2, 1.6 Hz), 6.88 (1H, tdd, J=7.6, 4.4, 1.6 Hz), 7.03 (1H,tt, J=7.6, 1.4 Hz), 7.07 (1H, ddd, J=11.2, 8.0, 1.6 Hz), 7.13 (1H, s),8.02 (1H, s).

Example 1206-[2-[4-Hydroxy-4-[(2-fluorophenyl)ethynyl]piperidino]ethyl]-1H-pyrazin-2-one

The title compound (96 mg, 77% yield) was obtained in the same manner asExample 118 from 146 mg of1-[2-(6-tert-butoxypyrazin-2-yl)ethyl]-4-[(2-fluorophenyl)ethynyl]piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.03-2.11 (2H, m), 2.14-2.22 (2H, m),2.60-2.68 (4H, m), 2.80 (2H, dd, J=6.6, 4.6 Hz), 2.85-2.94 (2H, m), 7.08(1H, ddd, J=9.2, 8.4, 0.8 Hz), 7.10 (1H, td, J=7.4, 1.0 Hz), 7.15 (1H,s), 7.28-7.35 (1H, m), 7.43 (1H, td, J=7.2, 1.6 Hz), 8.03 (1H, s).

Example 1211-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)-4-(2-methylphenoxymethyl)piperidine-4-carbonitrile

The title compound (37 mg, 92% yield) was obtained in the same manner asExample 118 from 47 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-methylphenoxymethyl)piperidine-4-carbonitrile.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.89 (2H, td, J=13.6, 3.4 Hz), 2.17 (2H,d, J=13.2 Hz), 2.28 (3H, s), 2.65 (2H, t, J=11.6 Hz), 3.14 (2H, d, J=12Hz), 3.86 (2H, s), 3.98 (2H, s), 6.76 (1H, d, J=8.4 Hz), 6.91 (1H, t,J=7.4 Hz), 7.13-7.18 (2H, m), 7.40-7.48 (1H, m), 7.62-7.67 (1H, m).

Example 1221-(2-Oxo-1,2-dihydro-3-pyridylmethyl)-4-(2-methylphenoxymethyl)piperidine-4-carbonitrile

After adding 10 ml of 4N hydrogen chloride/ethyl acetate to 273 mg of1-(tert-butoxycarbonyl)-4-cyano-4-(2-methylphenoxymethyl)piperidine, themixture was stirred for 6 hours at room temperature. The solvent wasdistilled off under reduced pressure to obtain 336 mg of4-cyano-4-(2-methylphenoxymethyl)piperidine hydrochloride.

After then adding 117 mg of the4-cyano-4-(2-methylphenoxymethyl)piperidine hydrochloride and 70 mg of2-oxo-1,2-dihydropyridine-3-carboxaldehyde [CAS No. 36404-89-4] to 10 mlof dichloromethane, the mixture was stirred for 20 minutes at roomtemperature. 139 mg of sodium triacetoxyborohydride was added and themixture was stirred overnight at room temperature. Saturated aqueoussodium bicarbonate solution was added to the reaction mixture andextraction was performed with ethyl acetate and chloroform. After dryingthe organic layer over magnesium sulfate, the solvent was distilled offunder reduced pressure. The obtained residue was purified by NH silicagel column chromatography (solvent: chloroform/methanol) to obtain thetitle compound (7 mg, 5% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.82 (2H, td, J=13.0, 3.4 Hz), 2.12-2.16(2H, m), 2.28 (s, 3H), 2.50-2.57 (2H, m), 3.00 (2H, d, J=9.6 Hz), 3.56(2H, s), 3.98 (2H, s), 6.31 (1H, t, J=6.6 Hz), 6.76 (1H, d, J=8.4 Hz),6.91 (1H, td, J=6.8, 0.8 Hz), 7.13-7.18 (2H, m), 7.33 (1H, dd, J=6.4,2.0 Hz), 7.50-7.52 (1H, m).

Example 1231-(2-Oxo-1,2-dihydro-3-pyridylmethyl)-4-(2-fluorophenoxymethyl)piperidine-4-carbonitrile

The title compound (8 mg, 6% yield) was obtained in the same manner asExample 122 from 103 mg of 4-cyano-4-(2-fluorophenoxymethyl)piperidinehydrochloride and 61 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.85 (2H, td, J=13.2, 3.2 Hz), 2.11 (2H,d, J=13.2 Hz), 2.53 (2H, t, J=11.0 Hz), 2.96-3.03 (2H, m), 3.56 (2H, s),4.05 (2H, s), 6.33 (1H, d, J=6.6 Hz), 6.94-7.02 (2H, m), 7.04-7.12 (2H,m), 7.34 (1H, dd, J=6.4, 1.6 Hz), 7.52-7.57 (1H, m).

Example 1243-[4-Fluoro-4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (9 mg, 12% yield) was obtained in the same manner asExample 122 from 60 mg of 4-fluoro-4-(2-fluorophenoxymethyl)piperidinehydrochloride and 36 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78-2.08 (4H, m), 2.52 (2H, t, J=11.6Hz), 2.78-2.83 (2H, m), 3.54 (2H, s), 4.05 (2H, d, J=18 Hz), 6.33 (1H,t, J=6.6 Hz), 6.89-7.11 (4H, m), 7.35 (1H, dd, J=6.4, 2.0 Hz), 7.57 (1H,d, J=6.8 Hz).

Example 1253-[4-Hydroxy-4-[2-(2-methylphenyl)ethyl]piperidino]methyl-1H-pyridin-2-one

The title compound (10 mg, 8% yield) was obtained in the same manner asExample 122 from 102 mg of4-hydroxy-4-[2-(2-methylphenyl)ethyl]piperidine hydrochloride and 64 mgof 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.71-1.76 (4H, m), 1.89-1.98 (2H, m),2.31 (3H, s), 2.67-2.79 (4H, m), 2.82-2.91 (2H, m), 3.69 (2H, s), 6.39(1H, t, J=6.6 Hz), 7.07-7.14 (4H, m), 7.38 (1H, dd, J=6.2, 1.8 Hz),7.74-7.82 (1H, m).

Example 1263-[4-Hydroxy-4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-1H-pyridin-2-one

The title compound (4 mg, 5% yield) was obtained in the same manner asExample 122 from 51 mg of4-hydroxy-4-[2-(2-fluorophenyl)ethyl]piperidine hydrochloride and 41 mgof 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60-1.84 (6H, m), 2.51-2.63 (2H, m),2.73-2.77 (4H, m), 3.57 (2H, s), 6.34 (1H, t, J=6.6 Hz), 6.97-7.07 (2H,m), 7.13-7.22 (2H, m), 7.34 (1H, td, J=6.8, 2.0 Hz), 7.58-7.64 (1H, m).

Example 1273-[4-(2-Fluorophenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-1H-pyridin-2-one

The title compound (6 mg, 7% yield) was obtained in the same manner asExample 122 from 74 mg of4-(2-fluorophenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidinehydrochloride and 32 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.69-1.88 (6H, m), 2.58-2.65 (6H, m),3.53 (2H, s), 3.92 (2H, s), 6.35 (1H, t, J=6.6 Hz), 6.85-6.93 (1H, m),6.95-7.09 (5H, m), 7.10-7.20 (2H, m), 7.31-7.35 (1H, m), 7.56-7.61 (1H,m).

Example 1283-[4-[2-(2-Fluorophenyl)ethyl]-4-(2-methylphenoxymethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (6 mg, 6% yield) was obtained in the same manner asExample 122 from 87 mg of4-(2-methylphenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidinehydrochloride and 38 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.57-1.88 (4H, m), 2.25 (3H, s),2.52-2.64 (6H, m), 3.45-3.51 (2H, m), 3.57 (2H, s), 3.87 (2H, s), 6.35(1H, t, J=6.6 Hz), 6.75-6.89 (2H, m), 6.96-7.09 (2H, m), 7.10-7.21 (4H,m), 7.35 (1H, d, J=6.2 Hz), 7.58-7.66 (1H, m).

Example 129anti-(E)-3-[9-[2-(2-Fluorophenyl)vinyl]-3-azabicyclo[3.3.1]non-3-yl]methyl-1H-pyridin-2-one

After suspending 200 mg ofanti-(E)-9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonanehydrochloride in 5 ml of 1,2-dichloroethane, 105 mg of2-oxo-1,2-dihydropyridine-3-carboxaldehyde and 241 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. Aqueous sodium carbonate solution was added to thereaction mixture and extraction was performed with ethyl acetate. Theorganic layer was washed with water and saturated brine in that orderand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: ethyl acetate/methanol) toobtain the title compound (207 mg, 83% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54-1.68 (3H, m), 1.86-1.91 (2H, m),1.92-2.03 (2H, m), 2.43-2.51 (3H, m), 2.65-2.79 (1H, m), 3.05-3.11 (2H,m), 3.42 (2H, s), 6.35 (1H, t, J=6.8 Hz), 6.55-6.67 (2H, m), 7.02 (1H,ddd, J=10.8, 8.0, 1.2 Hz), 7.09 (1H, dt, J=8.0, 1.2 Hz), 7.14-7.21 (1H,m), 7.33 (1H, dd, J=6.8, 2.0 Hz), 7.49 (1H, dt, J=8.0, 1.2 Hz), 7.61(1H, dd, J=6.8, 2.0 Hz), 12.62 (1H, br s).

Example 130anti-(E)-5-Chloro-3-[9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]non-3-yl]methyl-1H-pyridin-2-one

After dissolving 164 mg ofanti-(E)-3-(5-chloro-2-methoxypyridin-3-yl)methyl-9-[2-(2-fluorophenyl)vinyl]-3-azabicyclo[3.3.1]nonanein 5 ml of ethanol, 15 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was heated to reflux for 6 hours. Aqueous sodiumbicarbonate solution was added to the reaction solution and extractionwas performed with ethyl acetate. The organic layer was washed withwater and saturated brine in that order and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by NH silica gel columnchromatography (solvent: ethyl acetate/methanol) to obtain the titlecompound (141 mg, 89% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58-1.69 (3H, m), 1.88-2.05 (4H, m),2.48-2.63 (4H, m), 3.04-3.10 (2H, m), 3.41 (2H, s), 6.57-6.66 (2H, m),7.03 (1H, ddd, J=10.8, 8.0, 1.2 Hz), 7.09 (1H, dt, J=8.0, 1.2 Hz),7.15-7.21 (1H, m), 7.46-7.54 (3H, m).

Example 1313-[3-[2-(2-Fluorophenoxy)ethyl]azetidin-1-yl]methyl-1H-pyrazin-2-one

The title compound (23 mg, 51% yield) was obtained in the same manner asExample 118 from 54 mg of2-tert-butoxy-3-[3-[2-(2-fluorophenoxy)ethyl]azetidin-1-yl]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.11 (2H, q, J=6.0 Hz), 2.81-2.90 (1H,m), 3.19 (2H, t, J=8.0 Hz), 3.74 (2H, t, J=8.0 Hz), 3.93 (2H, s), 4.02(2H, t, J=6.0 Hz), 6.86-6.95 (2H, m), 7.01-7.09 (2H, m), 7.71 (1H, d,J=2.8 Hz), 7.75 (1H, d, J=2.8 Hz).

Example 1323-[3-(2-Fluorophenoxymethyl)pyrrolidino]methyl-1H-pyrazin-2-one oxalate

After dissolving 245 mg of3-[3-(2-fluorophenoxymethyl)pyrrolidino]methyl-2-methoxypyrazine in 5 mlof ethanol, 15 ml of 4N hydrogen chloride/ethyl acetate was added, andthe mixture was heated to reflux for 8 hours and then stirred overnightat 60° C. Aqueous sodium bicarbonate solution was added to the reactionsolution and extraction was performed with ethyl acetate. The organiclayer was washed with water and saturated brine in that order and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by NH silica gel columnchromatography (solvent: ethyl acetate/methanol). This was dissolved ina small amount of ethanol, and then 47 mg of oxalic acid anhydrous andethyl acetate were added and the precipitate was filtered out to obtainthe title compound (171 mg, 56% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.76-1.87 (1H, m), 2.12-2.22 (1H, m),2.78-2.90 (1H, m), 3.16-3.25 (1H, m), 3.32-3.44 (2H, m), 3.50-3.60 (1H,m), 4.02-4.14 (2H, m), 4.40 (2H, s), 6.93-6.99 (1H, m), 7.05-7.25 (3H,m), 7.36 (1H, d, J=4.0 Hz), 7.50 (1H, d, J=4.0 Hz).

Example 1333-[3-(2-Methoxyphenoxymethyl)pyrrolidino]methyl-1H-pyrazin-2-one oxalate

The title compound (167 mg, 38% yield) was obtained in the same manneras Example 132 from 352 mg of2-methoxy-3-[3-(2-methoxyphenoxymethyl)pyrrolidino]methyl-pyrazine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.77-1.87 (1H, m), 2.10-2.21 (1H, m),2.77-2.86 (1H, m), 3.14-3.25 (1H, m), 3.32-3.44 (2H, m), 3.51-3.62 (1H,m), 3.93-4.02 (2H, m), 4.42 (2H, s), 6.85-7.00 (4H, m), 7.36 (1H, d,J=4.0 Hz), 7.51 (1H, d, J=4.0 Hz).

Example 1343-[3-[2-(2-Fluorophenyl)ethyl]pyrrolidino]methyl-1H-pyrazin-2-one

The title compound (169 mg, 53% yield) was obtained in the same manneras Example 130 from 332 mg of3-[3-[2-(2-fluorophenyl)ethyl]pyrrolidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.53-1.63 (1H, m), 1.68-1.80 (2H, m),2.09-2.19 (1H, m), 2.21-2.33 (1H, m), 2.37-2.44 (1H, m), 2.57-2.70 (2H,m), 2.71-2.80 (1H, m), 2.82-2.90 (1H, m), 2.96-3.02 (1H, m), 3.94 (1H,d, J=15.2 Hz), 3.99 (1H, d, J=15.2 Hz), 6.97-7.08 (2H, m), 7.13-7.21(2H, m), 7.87 (1H, d, J=2.8 Hz), 7.90 (1H, d, J=2.8 Hz).

Example 1353-[3-[2-(2-Methoxyphenyl)ethyl]pyrrolidino]methyl-1H-pyrazin-2-oneoxalate

The title compound (235 mg, 61% yield) was obtained in the same manneras Example 132 from 314 mg of2-methoxy-3-[3-[2-(2-methoxyphenyl)ethyl]pyrrolidino]methyl-pyrazine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.57-1.72 (3H, m), 2.08-2.17 (1H, m),2.20-2.32 (1H m), 2.48-2.61 (2H, m), 2.92-3.00 (1H, m), 3.32-3.42 (2H,m), 3.48-3.56 (1H, m), 3.77 (3H, s), 4.40 (2H, s), 6.87 (1H, dt, J=7.2,1.2 Hz), 6.95 (1H, dd, J=8.0, 1.2 Hz), 7.12-7.21 (2H, m), 7.36 (1H, d,J=4.0 Hz), 7.51 (1H, d, J=4.0 Hz).

Example 1363-[3-(2-Methylphenoxymethyl)pyrrolidino]methyl-1H-pyrazin-2-one oxalate

The title compound (205 mg, 62% yield) was obtained in the same manneras Example 132 from 262 mg of2-methoxy-3-[3-(2-methylphenoxymethyl)pyrrolidino]methyl-pyrazine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.81-1.91 (1H, m), 2.13-2.23 (4H, m),2.78-2.90 (1H, m), 3.18-3.28 (1H, m), 3.36-3.44 (2H, m), 3.54-3.61 (1H,m), 3.94-4.05 (2H, m), 4.41 (2H, s), 6.85 (1H, dt, J=7.2, 0.8 Hz), 6.92(1H, d, J=8.0 Hz), 7.13-7.18 (2H, m), 7.36 (1H, d, J=4.0 Hz), 7.51 (1H,d, J=4.0 Hz).

Example 1372-[4-(2-Fluorophenoxymethyl)piperidino]methyl-3H-pyrimidin-4-one

After dissolving 282 mg of4-tert-butoxy-2-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrimidinein 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was allowed to stand at room temperature for 50minutes. Aqueous sodium bicarbonate solution was added to the reactionsolution and extraction was performed with ethyl acetate. The organiclayer was washed with water and brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. Diethyl ether was added to the residue and themixture was filtered to obtain the title compound (212 mg, 89% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45-1.57 (2H, m), 1.92-2.04 (3H, m),2.13-2.21 (2H, m), 2.77-2.84 (4H, m), 3.10-3.18 (2H, m), 3.91 (2H, d,J=6.4 Hz), 6.29 (1H, d, J=6.8 Hz), 6.86-6.93 (1H, m), 6.96 (1H, dt,J=8.4, 1.6 Hz), 7.03-7.11 (2H, m), 7.81 (1H, d, J=6.4 Hz).

Example 138(E)-3-[4-[2-(2-Fluorophenyl)vinyl]piperidino]methyl-1H-pyrazin-2-one

After dissolving 296 mg of(E)-3-[4-[2-(2-fluorophenyl)vinyl]piperidino]methyl-2-methoxypyrazine in5 ml of ethanol, 1 ml of thionyl chloride was added and the mixture washeated to reflux for 9 hours. Aqueous sodium carbonate solution wasadded to the reaction solution and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine inthat order and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. Ethyl acetate wasadded to the residue and the mixture was filtered to obtain the titlecompound (180 mg, 63% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61-1.73 (2H, m), 1.86-1.94 (2H, m),2.13-2.43 (3H, m), 3.02-3.10 (2H, m), 3.88 (2H, s), 6.22 (1H, dd,J=16.0, 6.8 Hz), 6.57 (1H, d, J=16.0 Hz), 7.02 (1H, ddd, J=10.8, 7.6,1.2 Hz), 7.08 (1H, dt, J=7.6, 1.2 Hz), 7.15-7.22 (1H, m), 7.43 (1H, dt,J=7.6, 1.6 Hz), 7.92 (1H, d, J=2.8 Hz), 7.94-7.98 (1H, m).

Example 1393-[4-[2-(2-Fluorophenyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (249 mg, 83% yield) was obtained in the same manneras Example 130 from 313 mg of2-[1-(3-methoxy-2-pyrazinylmethyl)piperidin-4-yl]-1-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.47 (2H, m), 1.78-1.85 (2H, m),2.01-2.14 (1H, m), 2.16-2.24 (2H, m), 2.89-2.96 (4H, m), 3.53 (2H, s),7.14 (1H, ddd, J=11.2, 8.4, 0.8 Hz), 7.23 (1H, ddd, J=8.4, 7.2, 0.8 Hz),7.41 (1H, d, J=2.8 Hz), 7.49-7.56 (1H, m), 7.71 (1H, br s), 7.83 (1H,dt, J=7.2, 1.6 Hz).

Example 1403-[4-[2-(2,3-Dihydrobenzofuran-7-yl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (131 mg, 55% yield) was obtained in the same manneras Example 130 from 249 mg of3-[4-[2-(2,3-dihydrobenzofuran-7-yl)ethyl]piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.32-1.46 (3H, m), 1.55-1.63 (2H, m),1.80-1.90 (2H, m), 2.22-2.31 (2H, m), 2.56-2.62 (2H, m), 2.96-3.03 (2H,m), 3.21 (2H, t, J=8.8 Hz), 3.84 (2H, s), 4.54 (2H, t, J=8.8 Hz), 6.78(1H, t, J=7.4 Hz), 6.92 (1H, d, J=7.4 Hz), 7.05 (1H, dd, J=7.4, 1.2 Hz),7.92 (1H, d, J=2.8 Hz), 7.99 (1H, d, J=2.8 Hz).

Example 141 3-[4-(2-Fluorobenzyloxy)piperidino]methyl-1H-pyrazin-2-one

The title compound (78 mg, 39% yield) was obtained in the same manner asExample 130 from 210 mg of3-[4-(2-fluorobenzyloxy)piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.92 (2H, m), 1.93-2.04 (2H, m),2.45-2.59 (2H, m), 2.83-2.94 (2H, m), 3.56-3.65 (1H, m), 3.86 (2H, s),4.61 (2H, s), 7.04 (1H, ddd, J=10.0, 8.0, 1.2 Hz), 7.15 (1H, td, J=8.0,1.2 Hz), 7.25-7.32 (1H, m), 7.44 (1H, td, J=8.0, 2.0 Hz), 7.92 (1H, d,J=2.8 Hz), 7.95 (1H, br s).

Example 1423-[4-(2-Fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (27 mg, 39% yield) was obtained in the same manner asExample 130 from 72 mg of3-[4-(2-fluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.58 (2H, m), 1.92-2.03 (3H, m),2.30-2.38 (2H, m), 3.04-3.10 (2H, m), 3.87 (2H, s), 3.89 (2H, d, J=6.0Hz), 6.87-6.98 (2H, m), 7.02-7.11 (2H, m), 7.91 (1H, d, J=2.8 Hz), 7.94(1H, br s).

Example 1433-[4-(2-Methoxyphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (83 mg, 58% yield) was obtained in the same manner asExample 130 from 148 mg of2-methoxy-3-[4-(2-methoxyphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.57 (2H, m), 1.95-2.05 (2H, m),2.10-2.40 (3H, m), 3.02-3.08 (2H, m), 3.84-3.90 (7H, m), 6.86-6.96 (4H,m), 7.92 (1H, d, J=2.8 Hz), 7.97 (1H, br s).

Example 1443-[4-[2-(2-Fluorophenyl)-2-hydroxyethyl]piperidino]methyl-1H-pyrazin-2-one

After dissolving 217 mg of3-[4-[2-(2-fluorophenyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-onein 30 ml of methanol, 25 mg of sodium borohydride was added whilestirring on ice, and the stirring was continued for 1 hour. Acetone wasadded to the reaction solution and the mixture was concentrated underreduced pressure. The residue was purified by NH silica gel columnchromatography (solvent: ethyl acetate/methanol) to obtain the titlecompound (179 mg, 82% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.50 (2H, m), 1.56-1.68 (2H, m),1.76-1.95 (3H, m), 2.24-2.34 (2H, m), 2.95-3.04 (2H, m), 3.84 (2H, s),5.12 (1H, dd, J=9.2, 4.4 Hz), 7.03 (1H, ddd, J=10.8, 8.4, 1.2 Hz), 7.16(1H, dt, J=7.6, 1.2 Hz), 7.23-7.29 (1H, m), 7.46 (1H, dt, J=7.6, 1.6Hz), 7.89 (1H, d, J=2.8 Hz), 7.94 (1H, d, J=2.8 Hz).

Example 1453-[4-[2-(2-Methoxyphenyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (115 mg, 57% yield) was obtained in the same manneras Example 130 from 211 mg of1-(2-methoxyphenyl)-2-[1-(3-methoxy-2-pyrazinylmethyl)piperidin-4-yl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.37-1.48 (2H, m), 1.81-1.88 (2H, m),2.04-2.16 (1H, m), 2.30-2.39 (2H, m), 2.93-3.02 (4H, m), 3.85 (2H, d,J=0.8 Hz), 3.91 (3H, s), 6.95-7.03 (2H, m), 7.46 (1H, ddd, J=8.4, 7.6,2.0 Hz), 7.64 (1H, dd, J=7.6, 2.0 Hz), 7.93 (1H, d, J=2.8 Hz), 7.98 (1H,br s).

Example 1463-[4-[2-(Benzofuran-7-yl)ethyl]piperidino]methyl-1H-pyrazin-2-one

After dissolving 218 mg of3-[4-[2-(benzofuran-7-yl)ethyl]piperidino]methyl-2-methoxypyrazine in 20ml of acetonitrile, 914 mg of sodium iodide and 0.39 ml ofchlorotrimethylsilane were added while stirring on ice, and the stirringwas continued for 30 minutes. After further stirring for 1 hour at roomtemperature, ice water and aqueous sodium carbonate solution were addedto the reaction solution and extraction was performed with ethylacetate. The organic layer was washed with water, aqueous sodiumthiosulfate solution and saturated brine in that order and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure, diethyl ether was added to the residue and the mixture wasfiltered to obtain the title compound (70 mg, 34% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.50 (3H, m), 1.70-1.78 (2H, m),1.82-1.94 (2H, m), 2.22-2.33 (2H, m), 2.90-2.97 (2H, m), 2.97-3.04 (2H,m), 3.85 (2H, s), 6.77 (1H, d, J=2.0 Hz), 7.08 (1H, dd, J=7.6, 1.2 Hz),7.16 (1H, t, J=7.6 Hz), 7.45 (1H, dd, J=7.6, 1.2 Hz), 7.62 (1H, d, J=2.0Hz), 7.91 (1H, d, J=2.8 Hz), 7.98 (1H, d, J=2.8 Hz).

Example 1473-[4-(2-Methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (155 mg, 69% yield) was obtained in the same manneras Example 130 from 236 mg of2-methoxy-3-[4-(2-methylphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.52-1.64 (2H, m), 1.90-2.00 (3H, m),2.22 (3H, s), 2.32-2.40 (2H, m), 3.04-3.11 (2H, m), 3.84 (2H, d, J=6.0Hz), 3.88 (2H, s), 6.79 (1H, d, J=7.6 Hz), 6.86 (1H, dt, J=7.6, 1.2 Hz),7.12-7.18 (2H, m), 7.92 (1H, d, J=2.8 Hz), 7.96 (1H, br s).

Example 1483-[4-[2-(2-Methoxyphenoxy)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (82 mg, 47% yield) was obtained in the same manner asExample 130 from 180 mg of3-[4-[2-(2-methoxyphenoxy)ethyl]piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.50 (2H, m), 1.64-1.78 (1H, m),1.80-1.91 (4H, m), 2.27-2.36 (2H, m), 2.97-3.05 (2H, m), 3.85 (2H, d,J=0.8 Hz), 3.86 (3H, s), 4.07 (2H, t, J=6.4 Hz), 6.86-6.96 (4H, m), 7.92(1H, d, J=2.8 Hz), 7.98 (1H, br s).

Example 1493-[3-(2-Methoxyphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (135 mg, 46% yield) was obtained in the same manneras Example 130 from 309 mg of2-methoxy-3-[3-(2-methoxyphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.18-1.30 (1H, m), 1.66-1.95 (3H, m),2.18-2.37 (3H, m), 2.89-2.97 (1H, m), 3.20-3.27 (1H, m), 3.81-3.88 (5H,m), 3.90-3.96 (2H, m), 6.85-6.97 (4H, m), 7.93 (1H, d, J=2.8 Hz), 7.98(1H, br s).

Example 1503-[3-(2-Fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (72 mg, 44% yield) was obtained in the same manner asExample 130 from 170 mg of3-[3-(2-fluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.24-1.37 (1H, m), 1.68-1.94 (3H, m),2.22-2.34 (3H, m), 2.90-2.98 (1H, m), 3.12-3.22 (1H, m), 3.82-3.98 (4H,m), 6.87-6.96 (2H, m), 7.01-7.10 (2H, m), 7.92 (1H, d, J=2.8 Hz), 7.95(1H, br s).

Example 1513-[4-(2,5-Difluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (221 mg, 74% yield) was obtained in the same manneras Example 130 from 309 mg of3-[4-(2,5-difluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-1.59 (2H, m), 1.92-2.04 (3H, m),2.29-2.38 (2H, m), 3.05-3.12 (2H, m), 3.86 (2H, d, J=5.6 Hz), 3.87 (2H,s), 6.55-6.61 (1H, m), 6.67 (1H, ddd, J=10.0, 6.8, 2.8 Hz), 7.01 (1H,ddd, J=10.8, 10.0, 5.6 Hz), 7.88 (2H, br s).

Example 152 3-[4-(2-Methylbenzyloxy)piperidino]methyl-1H-pyrazin-2-one

The title compound (151 mg, 55% yield) was obtained in the same manneras Example 130 from 286 mg of2-methoxy-3-[4-(2-methylbenzyloxy)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.79-1.90 (2H, m), 1.94-2.03 (2H, m),2.34 (3H, s), 2.46-2.57 (2H, m), 2.85-2.94 (2H, m), 3.55-3.62 (1H, m),3.85 (2H, d, J=0.8 Hz), 4.53 (2H, s), 7.15-7.24 (3H, m), 7.31-7.35 (1H,m), 7.89 (1H, d, J=2.8 Hz), 7.92 (1H, br s).

Example 1533-[4-(3-Methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (191 mg, 92% yield) was obtained in the same manneras Example 130 from 217 mg of2-methoxy-3-[4-(3-methylphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.59 (2H, m), 1.85-1.98 (3H, m),2.28-2.38 (5H, m), 3.03-3.10 (2H, m), 3.82 (2H, d, J=6.0 Hz), 3.87 (2H,s), 6.67-6.74 (2H, m), 6.77 (1H, d, J=7.6 Hz), 7.16 (1H, t, J=7.6 Hz),7.92 (1H, d, J=2.8 Hz), 7.95 (1H, br s).

Example 1543-[3-(2-Methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (50 mg, 37% yield) was obtained in the same manner asExample 130 from 140 mg of2-methoxy-3-[3-(2-methylphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.20-1.36 (1H, m) 1.70-1.94 (3H, m),2.18 (3H, s), 2.20-2.32 (3H, m), 2.93-3.01 (1H, m), 3.14-3.20 (1H, m),3.77-3.90 (4H, m), 6.76 (1H, d, J=7.6 Hz), 6.85 (1H, t, J=7.6 Hz),7.10-7.16 (2H, m), 7.92 (1H, d, J=2.4 Hz), 7.96 (1H, br s).

Example 1553-[3-[2-(2-Methoxyphenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (133 mg, 52% yield) was obtained in the same manneras Example 130 from 269 mg of3-[3-[2-(2-methoxyphenyl)ethyl]piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.97-1.10 (1H, m), 1.44-1.58 (2H, m),1.60-1.82 (3H, m), 1.88-2.06 (2H, m), 2.18-2.28 (1H, m), 2.53-2.69 (2H,m), 2.88-3.04 (2H, m), 3.80 (3H, s), 3.84 (2H, s), 6.83 (1H, d, J=7.6Hz), 6.87 (1H, td, J=7.6, 1.2 Hz), 7.08 (1H, dd, J=7.6, 1.6 Hz), 7.17(1H, td, J=7.6, 1.6 Hz), 7.93 (1H, d, J=2.8 Hz), 8.01 (1H, d, J=2.8 Hz).

Example 1563-[3-[2-(2-Fluorophenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (42 mg, 28% yield) was obtained in the same manner asExample 130 from 159 mg of3-[3-[2-(2-fluorophenyl)ethyl]piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.98-1.12 (1H, m), 1.48-1.58 (2H, m),1.60-1.82 (3H, m), 1.88-2.06 (2H, m), 2.19-2.29 (1H, m), 2.56-2.72 (2H,m), 2.88-3.00 (2H, m), 3.84 (2H, s), 6.99 (1H, ddd, J=8.8, 8.0, 1.2 Hz),7.04 (1H, td, J=7.6, 1.2 Hz), 7.11-7.19 (2H, m), 7.94 (1H, d, J=2.8 Hz),8.00 (1H, br s).

Example 157(E)-3-[4-[2-(3-Methyl-2-thienyl)vinyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (18 mg, 16% yield) was obtained in the same manner asExample 130 from 120 mg of(E)-2-methoxy-3-[4-[2-(3-methyl-2-thienyl)vinyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58-1.70 (2H, m), 1.82-1.92 (2H, m),2.10-2.40 (3H, m), 2.22 (3H, s), 3.00-3.08 (2H, m), 3.87 (2H, s), 5.93(1H, dd, J=16.0, 6.8 Hz), 6.53 (1H, d, J=16.0 Hz), 6.77 (1H, d, J=5.0Hz), 7.01 (1H, d, J=5.0 Hz), 7.93 (1H, d, J=2.4 Hz), 7.98 (1H, br s).

Example 1583-[4-(2-Chlorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (153 mg, 78% yield) was obtained in the same manneras Example 137 from 229 mg of2-tert-butoxy-3-[4-(2-chlorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.49-1.62 (2H, m), 1.95-2.06 (3H, m),2.31-2.40 (2H, m), 3.05-3.11 (2H, m), 3.88 (2H, s), 3.89 (2H, d, J=7.6Hz), 6.87-6.92 (2H, m), 7.20 (1H, ddd, J=8.4, 7.6, 1.6 Hz), 7.36 (1H,dd, J=8.4, 1.2 Hz), 7.91 (1H, d, J=2.8 Hz), 7.93 (1H, br s).

Example 1593-[4-[2-(2-Fluorophenoxy)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (85 mg, 41% yield) was obtained in the same manner asExample 137 from 244 mg of2-tert-butoxy-3-[4-[2-(2-fluorophenoxy)ethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.37-1.50 (2H, m), 1.66-1.90 (5H, m),2.26-2.38 (2H, m), 2.97-3.05 (2H, m), 3.86 (2H, s), 4.08 (2H, t, J=6.0Hz), 6.86-6.93 (1H, m), 6.96 (1H, td, J=8.4, 2.0 Hz), 7.02-7.11 (2H, m),7.92 (1H, d, J=2.8 Hz), 7.98 (1H, br s).

Example 1603-[4-(2-Fluorobenzyloxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (119 mg, 54% yield) was obtained in the same manneras Example 137 from 259 mg of2-tert-butoxy-3-[4-(2-fluorobenzyloxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.47 (2H, m), 1.68-1.90 (3H, m),2.24-2.35 (2H, m), 2.95-3.05 (2H, m), 3.37 (2H, d, J=6.4 Hz), 3.85 (2H,s), 4.57 (2H, s), 7.04 (1H, ddd, J=9.6, 7.8, 1.2 Hz), 7.14 (1H, td,J=7.8, 1.2 Hz), 7.25-7.31 (1H, m), 7.39 (1H, td, J=7.8, 1.6 Hz), 7.92(1H, d, J=2.4 Hz), 7.97 (1H, br s).

Example 1613-[4-(3-Methoxyphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (129 mg, 48% yield) was obtained in the same manneras Example 130 from 278 mg of2-methoxy-3-[4-(3-methoxyphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-1.60 (2H, m), 1.85-1.98 (3H, m),2.29-2.38 (2H, m), 3.03-3.10 (2H, m), 3.79 (3H, s), 3.82 (2H, d, J=6.0Hz), 3.87 (2H, s), 6.44-6.53 (3H, m), 7.18 (1H, t, J=8.0 Hz), 7.91 (1H,d, J=2.8 Hz), 7.93 (1H, br s).

Example 1623-[4-(3-Fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (138 mg, 72% yield) was obtained in the same manneras Example 137 from 223 mg of2-tert-butoxy-3-[4-(3-fluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-1.60 (2H, m), 1.86-1.97 (3H, m),2.29-2.38 (2H, m), 3.04-3.10 (2H, m), 3.81 (2H, d, J=5.6 Hz), 3.87 (2H,s), 6.60 (1H, dt, J=11.2, 2.4 Hz), 6.63-6.69 (2H, m), 7.22 (1H, dt,J=8.4, 7.2 Hz), 7.91 (1H, d, J=2.8 Hz), 7.92 (1H, br s).

Example 1633-[4-(2,4-Difluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (98 mg, 62% yield) was obtained in the same manner asExample 137 from 183 mg of2-tert-butoxy-3-[4-(2,4-difluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.58 (2H, m), 1.89-2.00 (3H, m),2.29-2.37 (2H, m), 3.04-3.10 (2H, m), 3.86 (2H, d, J=7.2 Hz), 3.87 (2H,s), 6.75-6.81 (1H, m), 6.82-6.93 (2H, m), 7.88-7.92 (2H, m).

Example 1643-[4-[2-(Trifluoromethyl)phenoxymethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (159 mg, 62% yield) was obtained in the same manneras Example 130 from 255 mg of2-methoxy-3-[4-[2-(trifluoromethyl)phenoxymethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-1.60 (2H, m), 1.94-2.05 (3H, m),2.32-2.41 (2H, m), 3.04-3.11 (2H, m), 3.88 (2H, s), 3.90 (2H, d, J=6.0Hz), 6.96 (1H, d, J=8.0 Hz), 7.01 (1H, t, J=8.0 Hz), 7.48 (1H, dt,J=8.0, 1.2 Hz), 7.57 (1H, dd, J=8.0, 1.2 Hz), 7.92 (1H, d, J=2.8 Hz),7.96 (1H, br s).

Example 1653-[4-(2-Ethoxyphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (52 mg, 34% yield) was obtained in the same manner asExample 137 from 178 mg of2-tert-butoxy-3-[4-(2-ethoxyphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43 (3H, t, J=6.8 Hz), 1.46-1.59 (2H,m), 1.94-2.04 (3H, m), 2.30-2.39 (2H, m), 3.03-3.10 (2H, m), 3.87 (2H,s), 3.88 (2H, d, J=4.4 Hz), 4.07 (2H, q, J=6.8 Hz), 6.87-6.94 (4H, m),7.91 (1H, d, J=2.8 Hz), 7.94 (1H, br s).

Example 1663-[4-(2-Cyanophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (121 mg, 79% yield) was obtained in the same manneras Example 137 from 180 mg of2-tert-butoxy-3-[4-(2-cyanophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.57 (2H, m), 1.99-2.11 (3H, m),2.31-2.40 (2H, m), 3.05-3.12 (2H, m), 3.88 (2H, s), 3.92 (2H, d, J=6.4Hz), 6.95 (1H, d, J=8.4 Hz), 7.02 (1H, dt, J=7.2, 0.8 Hz), 7.53 (1H,ddd, J=8.4, 7.2, 1.2 Hz), 7.57 (1H, dd, J=7.2, 1.2 Hz), 7.91 (2H, br s).

Example 1673-[4-[2-(Trifluoromethoxy)phenoxymethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (206 mg, 80% yield) was obtained in the same manneras Example 137 from 292 mg of2-tert-butoxy-3-[4-[2-(trifluoromethoxy)phenoxymethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.58 (2H, m), 1.93-2.04 (3H, m),2.31-2.40 (2H, m), 3.05-3.11 (2H, m), 3.87 (2H, d, J=6.0 Hz), 3.88 (2H,s), 6.92-6.99 (2H, m), 7.21-7.26 (2H, m), 7.90 (1H, d, J=2.4 Hz), 7.92(1H, br s).

Example 168(E)-3-[4-[2-(3-Chloro-2-thienyl)vinyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (167 mg, 78% yield) was obtained in the same manneras Example 137 from 250 mg of(E)-2-tert-butoxy-3-[4-[2-(3-chloro-2-thienyl)vinyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58-1.71 (2H, m), 1.84-1.92 (2H, m),2.20-2.42 (3H, m), 3.00-3.08 (2H, m), 3.88 (2H, s), 6.03 (1H, dd,J=16.0, 7.0 Hz), 6.61 (1H, dt, J=16.0, 1.0 Hz), 6.86 (1H, d, J=5.2 Hz),7.08 (1H, d, J=5.2 Hz), 7.92 (1H, d, J=2.8 Hz), 7.96 (1H, br s).

Example 1693-[4-[2-(3-Chloro-2-thienyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (140 mg, 72% yield) was obtained in the same manneras Example 137 from 226 mg of2-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-1-(3-chloro-2-thienyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.54 (2H, m), 1.85-1.93 (2H, m),2.06-2.26 (1H, m), 2.30-2.40 (2H, m), 2.95-3.04 (2H, m), 2.99 (2H, d,J=6.4 Hz), 3.86 (2H, s), 7.04 (1H, d, J=5.4 Hz), 7.55 (1H, d, J=5.4 Hz),7.92 (1H, d, J=2.8 Hz), 7.97 (1H, br s).

Example 1703-[4-[(2-Fluorophenyl)ethynyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (258 mg, 90% yield) was obtained in the same manneras Example 137 from 338 mg of2-tert-butoxy-3-[4-[(2-fluorophenyl)ethynyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.86-1.96 (2H, m), 1.99-2.09 (2H, m),2.44-2.68 (2H, m), 2.78-3.00 (3H, m), 3.87 (2H, s), 7.03-7.10 (2H, m),7.24-7.31 (1H, m), 7.39 (1H, dd, J=7.2, 2.0 Hz), 7.90 (2H, br s).

Example 171(E)-3-[4-[2-(2-Methylphenyl)vinyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (203 mg, 83% yield) was obtained in the same manneras Example 137 from 289 mg of(E)-2-tert-butoxy-3-[4-[2-(2-methylphenyl)vinyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61-1.73 (2H, m), 1.85-1.93 (2H, m),2.22-2.42 (3H, m), 2.33 (3H, s), 3.03-3.10 (2H, m), 3.87 (2H, s), 6.03(1H, dd, J=16.0, 7.2 Hz), 6.61 (1H, dd, J=16.0, 0.8 Hz), 7.12-7.19 (3H,m), 7.41 (1H, dd, J=8.0, 2.0 Hz), 7.90 (1H, d, J=2.8 Hz), 7.91 (1H, brs).

Example 1723-[4-[2-(3-Fluoro-2-thienyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (37 mg, 63% yield) was obtained in the same manner asExample 137 from 69 mg of2-tert-butoxy-3-[4-[2-(3-fluoro-2-thienyl)ethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.32-1.45 (3H, m), 1.58-1.66 (2H, m),1.78-1.86 (2H, m), 2.22-2.32 (2H, m), 2.72-2.79 (2H, m), 2.96-3.04 (2H,m), 3.85 (2H, s), 6.73 (1H, dd, J=5.6, 0.8 Hz), 6.98 (1H, dd, J=5.6, 4.0Hz), 7.92 (1H, d, J=2.8 Hz), 7.98 (1H, br s).

Example 173(E)-3-[4-[2-(3-Fluoro-2-thienyl)vinyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (54 mg, 26% yield) was obtained in the same manner asExample 137 from 242 mg of(E)-2-tert-butoxy-3-[4-[2-(3-fluoro-2-thienyl)vinyl]piperidino]methylpyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.57-1.69 (2H, m), 1.82-1.92 (2H, m),2.16-2.30 (1H, m), 2.31-2.40 (2H, m), 3.00-3.08 (2H, m), 3.87 (2H, s),5.93 (1H, dd, J=16.0, 6.8 Hz), 6.48 (1H, dd, J=16.0, 1.2 Hz), 6.74 (1H,d, J=5.6 Hz), 6.97 (1H, dd, J=5.6, 4.0 Hz), 7.93 (1H, d, J=2.8 Hz), 7.97(1H, br s).

Example 1743-[4-[2-(2-Chlorophenyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (114 mg, 59% yield) was obtained in the same manneras Example 137 from 224 mg of2-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-1-(2-chlorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.52 (2H, m), 1.84-1.91 (2H, m),2.06-2.18 (1H, m), 2.34 (2H, dt, J=12.0, 2.4 Hz), 2.92 (2H, d, J=6.4Hz), 2.97-3.04 (2H, m), 3.85 (2H, d, J=0.4 Hz), 7.30-7.44 (4H, m), 7.90(1H, d, J=2.8 Hz), 7.91-7.94 (1H, m).

Example 1753-[4-[1-(2-Fluorophenoxy)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (189 mg, 55% yield) was obtained in the same manneras Example 137 from 400 mg of2-tert-butoxy-3-[4-[1-(2-fluorophenoxy)ethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.29 (3H, d, J=6.0 Hz), 1.48-1.56 (2H,m), 1.69-1.88 (2H, m), 2.04-2.11 (1H, m), 2.25-2.35 (2H, m), 3.04-3.11(2H, m), 3.86 (2H, s), 4.01-4.09 (1H, m), 6.88-6.94 (1H, m), 6.96 (1H,td, J=8.4, 1.6 Hz), 7.02-7.11 (2H, m), 7.92 (1H, d, 2.4 Hz), 7.96 (1H,d, J=2.4 Hz).

Example 176(E)-3-[4-[2-(3-Fluorophenyl)vinyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (134 mg, 82% yield) was obtained in the same manneras Example 137 from 191 mg of(E)-2-tert-butoxy-3-[4-[2-(3-fluorophenyl)vinyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60-1.72 (2H, m), 1.84-1.92 (2H, m),2.21-2.41 (3H, m), 3.02-3.10 (2H, m), 3.88 (2H, s), 6.17 (1H, dd,J=16.0, 7.2 Hz), 6.38 (1H, d, J=16.0 Hz), 6.91 (1H, dt, J=8.4, 2.0 Hz),7.05 (1H, dt, J=10.4, 2.0 Hz), 7.10 (1H, d, J=7.6 Hz), 7.19-7.33 (1H,m), 7.92 (1H, d, J=2.8 Hz), 7.94 (1H, br s).

Example 1773-[4-[2-(2-Fluorophenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (103 mg, 44% yield) was obtained in the same manneras Example 137 from 275 mg of2-tert-butoxy-3-[4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.46 (3H, m), 1.56-1.63 (2H, m),1.79-1.90 (2H, m), 2.22-2.33 (2H, m), 2.63-2.70 (2H, m), 2.96-3.04 (2H,m), 3.85 (2H, s), 6.97-7.08 (2H, m), 7.14-7.20 (2H, m), 7.92 (1H, d,J=2.8 Hz), 7.97 (1H, d, J=2.8 Hz).

Example 1783-[4-[2-Fluoro-2-(2-fluorophenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

After dissolving 64 mg of 4-[2-fluoro-2-(2-fluorophenyl)ethyl]piperidinein 3 ml of tetrahydrofuran, 61 mg of3-tert-butoxy-2-pyrazinecarboxaldehyde and 90 mg of sodiumtriacetoxyborohydride were added while stirring, and the stirring wascontinued overnight at room temperature. A 1N sodium hydroxide solutionwas added to the reaction mixture and extraction was performed withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate). Twomilliliters of a 4N hydrogen chloride/ethyl acetate solution was addedto the obtained product while stirring, and the stirring was continuedfor 2.5 hours at room temperature. A 1N sodium hydroxide solution wasadded to the reaction solution and extraction was performed withdichloromethane. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. Diethyl ether/n-hexane was addedto the residue and the insoluble portion was filtered out to obtain thetitle compound (5 mg, 5% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-2.40 (9H, m), 2.96-3.07 (2H, m),3.86 (2H, s), 5.53 (1H, ddd, J=82.0, 9.2, 3.0 Hz), 6.97-7.43 (4H, m),7.92 (1H, d, J=2.4 Hz), 7.97 (1H, s).

Example 1793-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

After adding 5 ml of 4N hydrogen chloride/ethyl acetate to 334 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-fluorophenyl)ethanone,the mixture was stirred for 2 hours at room temperature. A 1N sodiumhydroxide solution and saturated aqueous sodium bicarbonate solutionwere added to the reaction solution for neutralization, and extractionwas performed with dichloromethane. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. Diethyl ether wasadded and the insoluble portion was filtered out to obtain the titlecompound (260 mg, 91% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.92 (2H, m), 1.93-2.01 (2H, m),2.29-2.39 (2H, m), 2.52-2.62 (1H, m), 3.00-3.08 (2H, m), 3.79 (2H, d,J=1.2 Hz), 3.84 (2H, s), 7.06 (1H, ddd, J=9.6, 7.8, 1.2 Hz), 7.11 (1H,td, J=7.8, 1.2 Hz), 7.17 (1H, td, J=7.8, 2.0 Hz), 7.24-7.30 (1H, m),7.87 (2H, br s).

After dissolving 527 mg of3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 100ml of dichloromethane, 0.44 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was concentrated under reduced pressure. Ethylacetate was added to the residue and the precipitate was filtered out(577 mg). A 400 mg portion thereof was recrystallized from 2.5 mlethanol/0.5 ml water to obtain a hydrochloride (279 mg).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.78-1.95 (2H, m), 2.06-2.15 (2H, m),2.78-2.90 (1H, m), 3.09-3.26 (2H, m), 3.54-3.68 (2H, m), 3.96 (2H, s),4.36 (2H, s), 7.10-7.18 (2H, m), 7.21-7.34 (2H, m), 7.40 (1H, d, J=4.0Hz), 7.53 (1H, d, J=4.0 Hz), 10.16 (1H, br s), 12.80 (1H, br s).

Example 1803-[4-[1-Hydroxy-2-(2-fluorophenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

After suspending 200 mg of3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 6ml of methanol, an excess of sodium borohydride was added while stirringat room temperature until completion of the reaction. Water was added tothe reaction solution and extraction was performed with dichloromethane.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. Diethyl ether was added and the insolubleportion was filtered out to obtain the title compound (112 mg, 56%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.70 (3H, m), 1.78-1.86 (1H, m),1.98-2.05 (1H, m), 2.24-2.34 (2H, m), 2.64 (1H, dd, J=7.6, 4.8 Hz), 3.00(1H, dd, J=7.6, 2.0 Hz), 3.04-3.12 (2H, m), 3.66-3.72 (1H, m), 3.86 (2H,s), 7.05 (1H, ddd, J=10.0, 8.0, 1.2 Hz), 7.12 (1H, td, J=8.0, 1.2 Hz),7.20-7.28 (2H, m), 7.92 (1H, d, J=2.8 Hz), 7.96 (1H, d, J=2.8 Hz).

Example 1814-[2-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-3H-pyrimidin-2-one

The title compound (190 mg, 76% yield) was obtained in the same manneras Example 137 from 293 mg of2-tert-butoxy-4-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrimidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38-1.51 (2H, m), 1.86-1.98 (3H, m),2.08-2.16 (2H, m), 2.73-2.82 (4H, m), 3.03-3.10 (2H, m), 3.88 (2H, d,J=6.4 Hz), 6.18 (1H, d, J=4.8 Hz), 6.86-6.98 (2H, m), 7.02-7.11 (2H, m),8.25 (1H, br s).

Example 1823-[4-(2-Methyl-5-phenylpyrrol-1-yl)methyl-piperidino]methyl-1H-pyrazin-2-one

The title compound (81 mg, 84% yield) was obtained in the same manner asExample 137 from 112 mg of2-tert-butoxy-3-[4-(2-methyl-5-phenylpyrrol-1-yl)methyl-piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.09 (2H, ddd, J=25.2, 12.6, 3.3 Hz),1.34-1.42 (2H, m), 1.42-1.50 (1H, m), 2.01 (2H, d, J=11.6 Hz), 2.30 (3H,s), 2.85 (2H, d, J=11.2 Hz), 3.70 (2H, s), 3.87 (2H, d, J=7.2 Hz), 5.95(1H, d, J=3.6 Hz), 6.08 (1H, d, J=3.6 Hz), 7.27-7.40 (5H, m), 7.75-7.81(2H, m).

Example 1833-[4-[2-(2-Chlorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (38 mg, 39% yield) was obtained in the same manner asExample 118 from 112 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-chlorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.82-2.04 (4H, m), 2.30-2.40 (2H, m),2.55-2.65 (1H, m), 3.00-3.08 (2H, m), 3.85 (2H, s), 3.91 (2H, s),7.18-7.28 (3H, m), 7.36-7.41 (1H, m), 7.88-7.93 (2H, m).

Example 1843-[4-[2-(2-Methylphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 153 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-methylphenyl)ethanone,the mixture was stirred for 5 hours at room temperature. Aqueous 1Nsodium hydroxide was added to the reaction solution and extraction wasperformed with dichloromethane. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. Diethyl ether wasadded and the insoluble portion was filtered out to obtain the titlecompound (66 mg, 51% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.79-1.95 (4H, m), 2.21 (3H, s),2.25-2.35 (2H, m), 2.50-2.59 (1H, m), 2.98-3.06 (2H, m), 3.77 (2H, s),3.84 (2H, s), 7.07-7.11 (1H, m), 7.14-7.22 (3H, m), 7.86-7.94 (2H, m).

Example 1854-Fluoro-2-[1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]-2,3-dihydroisoindol-1-one

The title compound (60 mg, 32% yield) was obtained in the same manner asExample 178 from 115 mg of4-fluoro-1-(piperidin-4-yl)-2,3-dihydro-isoindol-1-one hydrochloride and105 mg of 3-tert-butoxypyrazine-2-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.90-1.98 (4H, m), 2.45-2.52 (2H, m),3.13-3.18 (2H, m), 3.89 (2H, s), 4.38 (2H, s), 4.34-4.44 (1H, m), 7.09(1H, t, J=8.4 Hz), 7.45-7.57 (2H, m), 7.76-7.82 (1H, m), 7.82-7.87 (1H,m).

Example 1864-Fluoro-2-[1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methyl-isoindole-1,3-dione

The title compound (3 mg, 35% yield) was obtained in the same manner asExample 137 from 10 mg of2-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]methyl-4-fluoro-isoindole-1,3-dione.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.50 (2H, ddd, J=24.6, 11.8, 3.6 Hz),1.74-1.80 (2H, m), 1.85-1.95 (1H, m), 2.22-2.29 (2H, m), 2.98-3.03 (2H,m), 3.62 (2H, d, J=7.2 Hz), 3.83 (2H, s), 7.36-7.41 (1H, m), 7.66-7.76(3H, m), 7.88-7.91 (1H, m).

Example 1873-[4-[3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-1H-pyrazin-2-one

The title compound (47 mg, 89% yield) was obtained in the same manner asExample 137 from 61 mg of2-tert-butoxy-3-[4-[3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.09-2.28 (4H, m), 2.49 (2H, t, J=10.4Hz), 3.05-3.18 (3H, m), 3.88 (2H, s), 7.21-7.27 (1H, m), 7.29 (1H, dd,J=7.8, 1.0 Hz), 7.47-7.53 (1H, m), 7.78-7.82 (1H, m), 7.82-7.86 (1H, m),8.06 (1H, td, J=7.2, 1.6 Hz).

Example 1883-[4-[3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-1H-pyrazin-2-one

The title compound (11 mg, 100% yield) was obtained in the same manneras Example 137 from 12 mg of2-tert-butoxy-3-[4-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.10-2.31 (4H, m), 2.49 (2H, d, J=11.0Hz), 3.05-3.18 (3H, m), 3.88 (2H, s), 7.21 (1H, tdd, J=8.4, 2.6, 1.0Hz), 7.46 (1H, td, J=8.0, 5.6 Hz), 7.78 (1H, ddd, J=9.2, 2.4, 1.2 Hz),7.78-7.83 (1H, m), 7.83-7.88 (1H, m), 7.88 (1H, ddd, J=4.0, 1.6, 0.8Hz).

Example 1893-[4-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-1H-pyrazin-2-one

The title compound (12 mg, 87% yield) was obtained in the same manner asExample 137 from 16 mg of2-tert-butoxy-3-[4-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.10-2.29 (4H, m), 2.50 (2H, t, J=10.2Hz), 3.05-3.15 (3H, m), 3.89 (2H, s), 7.14-7.20 (2H, m), 7.80-7.88 (2H,m), 8.05-8.10 (2H, m).

Example 1903-[4-[2-(2-Fluorophenyl)-1-methoxyethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (47 mg, 40% yield) was obtained in the same manner asExample 118 from 138 mg of2-tert-butoxy-3-[4-[2-(2-fluorophenyl)-1-methoxyethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.78 (4H, m), 1.89-1.97 (1H, m),2.20-2.28 (2H, m), 2.76 (1H, dd, J=14.4, 8.0 Hz), 2.88 (1H, dd, J=14.4,6.4 Hz), 3.00-3.10 (2H, m), 3.19-3.27 (1H, m), 3.24 (3H, s), 3.82 (1H,d, J=14.4 Hz), 3.86 (1H, d, J=14.4 Hz), 7.02 (1H, ddd, J=9.8, 8.4, 1.2Hz), 7.08 (1H, td, J=7.6, 1.2 Hz), 7.18-7.28 (2H, m), 7.92 (1H, d, J=2.8Hz), 7.98 (1H, d, J=2.8 Hz).

Example 1913-[4-[2-(3-Fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (65 mg, 58% yield) was obtained in the same manner asExample 118 from 132 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(3-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.76-1.96 (4H, m), 2.26-2.37 (2H, m),2.50-2.58 (1H, m), 2.98-3.06 (2H, m), 3.75 (2H, s), 3.83 (2H, s),6.88-6.93 (1H, m), 6.94-7.00 (2H, m), 7.26-7.33 (1H, m), 7.88 (2H, brs).

Example 1923-[4-[2-(3-Methylphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (70 mg, 76% yield) was obtained in the same manner asExample 118 from 108 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(3-methylphenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.76-1.93 (4H, m), 2.26-2.35 (2H, m),2.34 (3H, s), 2.50-2.59 (1H, m), 2.96-3.05 (2H, m), 3.71 (2H, s), 3.83(2H, s), 6.96-7.01 (2H, m), 7.08 (1H, d, J=7.6 Hz), 7.22 (1H, t, J=7.6Hz), 7.86-7.94 (2H, m).

Example 1933-[4-[2-(2-Methoxyphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

After dissolving 249 mg of1-(1-benzylpiperidin-4-yl)-2-(2-methoxyphenyl)ethanone in 4 ml of1,2-dichloroethane, 0.1 ml of 1-chloroethyl chloroformate was addedwhile stirring on ice and the mixture was heated to reflux for 1 hour.The reaction solution was concentrated under reduced pressure, 4 ml ofmethanol was added to the residue, and heating to reflux was continuedfor 1 hour. The reaction solution was concentrated under reducedpressure, ethyl acetate was added to the residue and the precipitate wasfiltered out. It was then suspended in 3 ml of dichloromethane, 90 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 132 mg of sodiumtriacetoxyborohydride were added while stirring on ice, and the stirringwas continued overnight at room temperature. Aqueous 1N sodium hydroxidewas added to the reaction mixture and extraction was performed withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate).

After adding 2 ml of 4N hydrogen chloride/ethyl acetate to the obtained1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-methoxyphenyl)ethanone,the mixture was stirred overnight at room temperature. Aqueous 1N sodiumhydroxide was added to the reaction solution for adjustment to pH 8, andextraction was performed with dichloromethane. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. Diethyl etherwas added and the precipitate was filtered out to obtain the titlecompound (89 mg, 34% yield, 3 steps).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.98 (4H, m), 2.28-2.38 (2H, m),2.50-2.60 (1H, m), 2.97-3.06 (2H, m), 3.73 (2H, s), 3.79 (3H, s), 3.84(2H, s), 6.87 (1H, d, J=8.0 Hz), 6.93 (1H, td, J=7.6, 1.2 Hz), 7.11 (1H,dd, J=7.6, 1.6 Hz), 7.24-7.29 (1H, m), 7.91 (1H, br s), 7.93 (1H, br s).

Example 1943-[4-[2-(2,5-Difluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (92 mg, 66% yield) was obtained in the same manner asExample 118 from 162 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2,5-difluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.92 (2H, m), 1.94-2.02 (2H, m),2.30-2.40 (2H, m), 2.52-2.62 (1H, m), 3.00-3.09 (2H, m), 3.77 (2H, d,J=1.2 Hz), 3.85 (2H, s), 6.86-7.05 (3H, m), 7.88 (2H, br s).

Example 1953-[4-[2-(2,6-Difluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (32 mg, 86% yield) was obtained in the same manner asExample 118 from 43 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2,6-difluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.84-1.97 (2H, m), 1.98-2.06 (2H, m),2.32-2.43 (2H, m), 2.56-2.66 (1H, m), 3.01-3.10 (2H, m), 3.83 (2H, s),3.86 (2H, s), 6.86-6.94 (2H, m), 7.20-7.28 (1H, m), 7.89 (2H, br s).

Example 196 3-[4-(2-Phenylacetyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (24 mg, 53% yield) was obtained in the same manner asExample 118 from 54 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-phenylethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.77-1.92 (4H, m), 2.27-2.34 (2H, m),2.51-2.58 (1H, m), 2.98-3.04 (2H, m), 3.76 (2H, s), 3.83 (2H, s),7.17-7.20 (2H, m), 7.26-7.36 (3H, m), 7.88 (2H, br s).

Example 1973-[4-[2-(2,4-Difluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (16 mg, 63% yield) was obtained in the same manner asExample 118 from 33 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2,4-difluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.88-1.96 (2H, m), 1.98-2.06 (2H, m),2.40-2.64 (3H, m), 3.06-3.14 (2H, m), 3.76 (2H, s), 3.90 (2H, s),6.80-6.88 (2H, m), 7.13 (1H, dd, J=8.2, 6.4 Hz), 7.81 (2H, br s).

Example 198 3-[4-(Phenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (150 mg, 82% yield) was obtained in the same manneras Example 137 from 217 mg of2-tert-butoxy-3-(4-phenoxymethylpiperidino)methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.48-1.61 (2H, m), 1.86-1.98 (3H, m),2.29-2.38 (2H, m), 3.04-3.11 (2H, m), 3.83 (2H, d, J=6.0 Hz), 3.87 (2H,s), 6.87-6.91 (2H, m), 6.93-6.97 (1H, m), 7.26-7.32 (2H, m), 7.90 (1H,d, J=2.8 Hz), 7.93 (1H, br s).

Example 1993-[4-(4-Fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (105 mg, 60% yield) was obtained in the same manneras Example 137 from 204 mg of2-tert-butoxy-3-[4-(4-fluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-1.60 (2H, m), 1.84-1.97 (3H, m),2.29-2.38 (2H, m), 3.04-3.11 (2H, m), 3.79 (2H, d, J=6.0 Hz), 3.87 (2H,s), 6.79-6.85 (2H, m), 6.93-7.01 (2H, m), 7.91 (1H, d, J=2.8 Hz), 7.93(1H, br s).

Example 2003-[4-[2-(2,3-Difluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (12 mg, 27% yield) was obtained in the same manner asExample 118 from 44 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2,3-difluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.87-2.06 (4H, m), 2.42-2.52 (2H, m),2.58-2.66 (1H, m), 3.06-3.16 (2H, m), 3.83 (2H, s), 3.89 (2H, s),6.90-6.94 (1H, m), 7.02-7.14 (2H, m), 7.83 (2H, br s).

Example 2013-[4-(2,6-Difluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (141 mg, 78% yield) was obtained in the same manneras Example 137 from 213 mg of2-tert-butoxy-3-[4-(2,6-difluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.58 (2H, m), 1.86-2.02 (3H, m),2.30-2.39 (2H, m), 3.03-3.10 (2H, m), 3.88 (2H, s), 3.98 (2H, d, J=6.4Hz), 6.85-6.99 (3H, m), 7.92 (1H, d, J=2.8 Hz), 7.96 (1H, br s).

Example 2023-[4-[1-Hydroxyimino-2-(2-fluorophenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

After suspending 150 mg of3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 3ml of ethanol, 47 mg of hydroxylamine hydrochloride and 193 mg of sodiumcarbonate were added while stirring and the mixture was heated to refluxfor 1 hour. Water and saturated aqueous ammonium chloride solution wereadded to the reaction solution for adjustment to pH 7, and extractionwas performed with dichloromethane. The organic layer was washed withbrine and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. Diethyl ether was added andthe insoluble portion was filtered out to obtain the title compound (109mg, 70% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68-1.88 (4H, m), 1.97-2.36 (3H, m),2.98-3.08 (2H, m), 3.53-3.84 (4H, m), 7.01-7.12 (2H, m), 7.18-7.28 (2H,m), 7.86-7.93 (2H, m).

Example 2033-[4-[2-(2-Fluorophenyl)-1-(methoxyimino)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (80 mg, 49% yield) was obtained in the same manner asExample 202 from 150 mg of3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one and 57mg of O-methylhydroxylamine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.68-1.86 (4H, m), 2.15-2.50 (3H, m),2.94-3.04 (2H, m), 3.52-3.88 (7H, m), 7.00-7.30 (4H, m), 7.90 (1H, d,J=2.8 Hz), 7.95 (1H, br s).

Example 2043-[4-(2-Fluorophenoxymethyl)piperidino]methyl-1H-quinoxalin-2-one

The title compound (116 mg, 77% yield) was obtained in the same manneras Example 118 from 174 mg of2-tert-butoxy-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-quinoxaline.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.50-1.62 (2H, m), 1.86-1.99 (3H, m),2.23-2.32 (2H, m), 3.22-3.29 (2H, m), 3.88 (2H, d, J=6.4 Hz), 3.90 (2H,s), 6.85-6.91 (1H, m), 6.95 (1H, dt, J=8.0, 1.6 Hz), 7.01-7.10 (2H, m),7.31-7.38 (2H, m), 7.52 (1H, dt, J=8.0, 1.6 Hz), 7.92 (1H, dd, J=8.0,0.8 Hz).

Example 2053-[4-(2-Methoxyphenoxymethyl)piperidino]methyl-1H-quinoxalin-2-one

2-tert-Butoxy-3-[4-(2-methoxyphenoxymethyl)piperidino]methylquinoxaline(181 mg, 64% yield) was obtained in the same manner as Example 1 from150 mg of 3-tert-butoxyquinoxaline-2-carboxaldehyde and 185 mg of4-(2-methoxyphenoxymethyl)piperidine hydrochloride.

This was subjected to the same process as in Example 118 to obtain thetitle compound (126 mg, 79% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.49-1.62 (2H, m), 1.88-2.04 (3H, m),2.22-2.32 (2H, m), 3.20-3.27 (2H, m), 3.85 (3H, s), 3.87 (2H, d, J=7.2Hz), 3.88 (2H, s), 6.87-6.94 (4H, m), 7.26-7.32 (1H, m), 7.35 (1H, dt,J=8.4, 1.6 Hz), 7.51 (1H, dt, J=8.4, 1.6 Hz), 7.92 (1H, dd, J=8.4, 1.6Hz).

Example 2063-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-1H-quinoxalin-2-one

The title compound (109 mg, 84% yield) was obtained in the same manneras Example 118 from 150 mg of1-[1-(3-tert-butoxy-2-quinoxalinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.83-1.95 (4H, m), 2.24-2.33 (2H, m),2.46-2.55 (1H, m), 3.19-3.26 (2H, m), 3.79 (2H, s), 3.86 (2H, s),7.02-7.07 (1H, m), 7.10 (1H, dt, J=7.6, 1.2 Hz), 7.16 (1H, dt, J=8.0,2.0 Hz), 7.20-7.28 (2H, m), 7.35 (1H, dt, J=8.0, 1.2 Hz), 7.51 (1H, dt,J=8.0, 1.2 Hz), 7.92 (1H, dd, J=8.0, 1.2 Hz).

Example 2073-[4-[2-(2-Methylphenyl)acetyl]piperidino]methyl-1H-quinoxalin-2-one

After suspending 183 mg of 2-(2-methylphenyl)-1-(piperidin-4-yl)ethanonehydrochloride in 3 ml of dichloromethane, 150 mg of2-tert-butoxyquinoxaline-3-carboxaldehyde and 180 mg of sodiumtriacetoxyborohydride were added while stirring, and the stirring wascontinued overnight at room temperature. Aqueous sodium bicarbonatesolution was added to the reaction mixture and extraction was performedwith ethyl acetate. The organic layer was washed with water andsaturated brine in that order and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate) to obtain1-[1-(3-tert-butoxy-2-quinoxalinylmethyl)piperidin-4-yl]-2-(2-methylphenyl)ethanone(177 mg, 63% yield).

This was dissolved in 3 ml of ethyl acetate, and then 3 ml of 4Nhydrogen chloride/ethyl acetate was added and the mixture was allowed tostand at room temperature for 30 minutes. Aqueous sodium bicarbonatesolution was added to the reaction solution and extraction was performedwith dichloromethane. The extract was dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Theresidue was purified by NH silica gel column chromatography (solvent:ethyl acetate/methanol), diethyl ether was added and the insolubleportion was filtered out to obtain the title compound (177 mg, 79%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.83-1.96 (4H, m), 2.21 (3H, s),2.22-2.30 (2H, m), 2.44-2.53 (1H, m), 3.19-3.26 (2H, m), 3.77 (2H, s),3.86 (2H, s), 7.06-7.11 (1H, m), 7.13-7.19 (3H, m), 7.24-7.28 (1H, m),7.35 (1H, dt, J=8.0, 0.8 Hz), 7.51 (1H, dt, J=8.0, 1.2 Hz), 7.92 (1H,dd, J=8.0, 1.2 Hz).

Example 2083-[3-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (143 mg, 87% yield) was obtained in the same manneras Example 118 from 193 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-3-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.54 (1H, m), 1.66-1.79 (1H, m),1.80-1.88 (1H, m), 2.02-2.11 (1H, m), 2.20-2.29 (1H, m), 2.39-2.48 (1H,m), 2.84-2.96 (2H, m), 3.03-3.10 (1H, m), 3.74-3.88 (4H, m), 7.05 (1H,ddd, J=9.6, 7.8, 1.2 Hz), 7.09 (1H, td, J=7.8, 1.2 Hz), 7.15 (1H, td,J=7.8, 2.0 Hz), 7.22-7.30 (1H, m), 7.79 (1H, br s), 7.83 (1H, d, J=2.8Hz).

Example 2093-[2-[2-(2-Fluorophenoxy)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (10 mg, 78% yield) was obtained in the same manner asExample 137 from 15 mg of2-tert-butoxy-3-[2-[2-(2-fluorophenoxy)ethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.51-1.56 (1H, m), 1.62-1.80 (4H, m),1.89-1.95 (1H, m), 1.97-2.06 (1H, m), 2.23-2.31 (1H, m), 2.49-2.55 (1H,m), 2.88-2.92 (1H, m), 2.92-3.00 (1H, m), 3.84 (1H, d, J=15.6 Hz),4.01-4.16 (2H, m), 4.22 (1H, d, J=15.6 Hz), 6.86-6.89 (2H, m), 7.02-7.09(2H, m), 7.88 (1H, d, J=2.8 Hz), 7.91 (1H, br s).

Example 2103-[4-Hydroxy-4-(2-methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (23 mg, 100% yield) was obtained in the same manneras Example 137 from 27 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-methylphenoxymethyl)piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.86-1.92 (4H, m), 2.25 (3H, s), 2.78(2H, td, J=10.6, 5.2 Hz), 2.85-2.91 (2H, m), 3.85 (2H, s), 3.92 (2H, s),6.81 (1H, d, J=7.6 Hz), 6.88-6.93 (1H, m), 7.15-7.19 (2H, m), 7.84-7.88(2H, m).

Example 2113-[4-Hydroxy-4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (23 mg, 100% yield) was obtained in the same manneras Example 137 from 27 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-fluorophenoxymethyl)piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.79-1.93 (4H, m), 2.77 (2H, td, J=11.6,3.2 Hz), 2.84-2.90 (2H, m), 3.90 (2H, s), 3.92 (2H, s), 6.91-6.99 (2H,m), 7.04-7.12 (2H, m), 7.88 (2H, s).

Example 2123-[4-Hydroxy-4-(2-methyl-5-phenylpyrrol-1-yl)methyl-piperidino]methyl-1H-pyrazin-2-one

The title compound (32 mg, 88% yield) was obtained in the same manner asExample 137 from 42 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-methyl-5-phenylpyrrol-1-yl)methyl-piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.19-1.43 (6H, m), 2.37 (3H, s),2.40-2.50 (2H, m), 2.52-2.66 (2H, m), 3.74 (2H, s), 6.00 (1H, dd, J=3.2,2.4 Hz), 6.13 (1H, d, J=3.2 Hz), 7.26-7.34 (3H, m), 7.36-7.42 (2H, m),7.84 (2H, br s).

Example 2132-Fluoro-N-[4-hydroxy-1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]benzamide

The title compound (8 mg, 51% yield) was obtained in the same manner asExample 137 from 18 mg ofN-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-hydroxypiperidin-4-yl]methyl-2-fluorobenzamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.82 (2H, m), 2.04-2.31 (4H, m),2.73-2.85 (2H, m), 3.55 (2H, d, J=6.0 Hz), 3.91 (2H, s), 6.76-6.83 (1H,m), 7.43-7.48 (2H, m), 7.51-7.56 (1H, m), 7.79-7.82 (2H, m), 7.89 (1H,s).

Example 2142-Fluoro-N-(2-fluorobenzoyl)-N-[4-hydroxy-1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]benzamide

The title compound (8 mg, 51% yield) was obtained in the same manner asExample 137 from 18 mg ofN-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-hydroxypiperidin-4-yl]methyl-2-fluoro-N-(2-fluorobenzoyl)benzamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.96-2.05 (2H, m), 2.44-2.52 (2H, m),2.60-2.70 (2H, m), 2.88-2.91 (2H, m), 3.87 (2H, s), 4.12 (2H, dd, J=6.4,1.2 Hz), 7.07-7.20 (2H, m), 7.23-7.29 (1H, m), 7.42-7.65 (3H, m),7.72-7.78 (1H, m), 7.79-7.84 (1H, m), 7.94 (1H, td, J=7.8, 1.8 Hz),8.04-8.09 (1H, m).

Example 2153-[4-(3-Phenyl-1,2,4-oxadiazol-5-yl)piperidino]methyl-1H-pyrazin-2-one

The title compound (48 mg, 93% yield) was obtained in the same manner asExample 137 from 60 mg of2-tert-butoxy-3-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.09-2.27 (4H, m), 2.48 (2H, t, J=10.2Hz), 3.05-3.16 (3H, m), 3.87 (2H, s), 7.45-7.53 (3H, m), 7.73 (1H, brs), 7.79-7.82 (1H, m), 8.06-8.09 (2H, m).

Example 2163-[4-(Ethoxycarbonyl)-4-(2-phenylethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (24 mg, 100% yield) was obtained in the same manneras Example 137 from 20 mg of ethyl1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-phenylethyl)piperidine-4-carboxylate.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.30 (3H, t, J=7.2 Hz), 1.60-1.68 (2H,m), 1.83-1.88 (2H, m), 2.30 (2H, d, J=12.8 Hz), 2.41 (2H, t, J=11.6 Hz),2.49-2.54 (2H, m), 2.85-2.92 (2H, m), 3.82 (2H, s), 4.19 (2H, q, J=7.2Hz), 7.13 (2H, d, J=6.8 Hz), 7.19 (1H, t, J=7.4 Hz), 7.28 (2H, d, J=7.2Hz), 7.80-7.86 (2H, m).

Example 2173-[4-(2-Fluorophenyl)ethynyl-4-hydroxypiperidino]methyl-1H-pyrazin-2-one

The title compound (79 mg, 91% yield) was obtained in the same manner asExample 137 from 102 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-[(2-fluorophenyl)ethynyl]piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.05-2.11 (2H, m), 2.12-2.20 (2H, m),2.75 (2H, t, J=9.0 Hz), 2.90-2.97 (2H, m), 3.89 (2H, s), 7.06-7.13 (2H,m), 7.29-7.36 (1H, m), 7.39-7.44 (1H, m), 7.79 (1H, br s), 7.82-7.85(1H, m).

Example 2183-[4-(2-Methylphenyl)ethynyl-4-hydroxypiperidino]methyl-1H-pyrazin-2-one

The title compound (65 mg, 74% yield) was obtained in the same manner asExample 137 from 103 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-[(2-methylphenyl)ethynyl]piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.05-2.10 (2H, m), 2.12-2.18 (2H, m),2.43 (3H, s), 2.74 (2H, d, J=10.2 Hz), 2.90-2.99 (2H, m), 3.87 (2H, d,J=3.2 Hz), 7.11-7.17 (1H, m), 7.18-7.27 (2H, m), 7.39 (1H, d, J=7.6 Hz),7.68-7.76 (1H, m), 7.76-7.82 (1H, m).

Example 2193-[4-Hydroxymethyl-4-(2-phenylethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (50 mg, 94% yield) was obtained in the same manner asExample 137 from 62 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-phenylethyl)piperidine-4-methanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60-1.77 (6H, m), 2.53-2.74 (6H, m),3.59 (2H, s), 3.86 (2H, s), 7.12-7.21 (3H, m), 7.26-7.31 (2H, m),7.86-7.94 (2H, m).

Example 2203-[4-[2-(2-Fluorophenyl)ethyl]-4-hydroxypiperidino]methyl-1H-pyrazin-2-one

The title compound (5 mg, 31% yield) was obtained in the same manner asExample 137 from 19 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-[2-(2-fluorophenyl)ethyl]piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.86 (6H, m), 2.68-2.83 (6H, m),3.90 (2H, s), 6.98-7.09 (2H, m), 7.14-7.22 (2H, m), 7.89-7.93 (2H, m).

Example 2213-[4-Cyano-4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (46 mg, 97% yield) was obtained in the same manner asExample 137 from 55 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-(2-fluorophenoxymethyl)piperidine-4-carbonitrile.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.91 (2H, td, J=13.6, 3.4 Hz), 2.09-2.20(2H, m), 2.58-2.68 (2H, m), 3.10-3.17 (2H, m), 3.84 (2H, s), 4.06 (2H,s), 6.95-7.02 (2H, m), 7.04-7.13 (2H, m), 7.40-7.49 (1H, m), 7.62-7.68(1H, m).

Example 2223-[4-Hydroxy-4-[2-(2-methylphenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (100 mg, 85% yield) was obtained in the same manneras Example 137 from 138 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-[2-(2-methylphenyl)ethyl]piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.73-1.77 (4H, m), 1.84 (2H, td, J=13.0,4.4 Hz), 2.32 (3H, s), 2.68-2.75 (4H, m), 2.79-2.87 (2H, m), 3.90 (2H,s), 7.09-7.17 (4H, m), 7.87 (2H, br s).

Example 2233-[4-Fluoro-4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (11 mg, 71% yield) was obtained in the same manner asExample 137 from 18 mg of2-tert-butoxy-3-[4-fluoro-4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.90-2.14 (4H, m), 2.64 (2H, td, J=12.0,2.6 Hz), 2.93-2.98 (2H, m), 3.87 (2H, s), 4.06 (2H, d, J=30.0 Hz),6.91-7.01 (2H, m), 7.03-7.11 (2H, m), 7.63 (1H, br s), 7.75 (1H, d,J=3.2 Hz).

Example 2243-[4-(2-Fluorophenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (26 mg, 81% yield) was obtained in the same manner asExample 137 from 36 mg of2-tert-butoxy-3-[4-(2-fluorophenoxymethyl)-4-[2-(2-fluorophenyl)ethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.75-1.90 (6H, m), 2.61-2.66 (2H, m),2.68-2.76 (4H, m), 3.88 (2H, s), 3.93 (2H, s), 6.90-7.20 (8H, m),7.82-7.86 (2H, m).

Example 2253-[4-[2-(2-Fluorophenyl)ethyl]-4-(2-methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (14 mg, 75% yield) was obtained in the same manner asExample 137 from 21 mg of2-tert-butoxy-3-[4-[2-(2-fluorophenyl)ethyl]-4-(2-methylphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60-1.91 (4H, m), 2.26 (3H, s),2.60-2.65 (2H, m), 2.72-2.77 (4H, m), 3.79-3.86 (2H, m), 3.88 (4H, s),6.76-6.91 (2H, m), 6.97-7.07 (2H, m), 7.09-7.20 (4H, m), 7.88 (2H, brs).

Example 2263-[2-(2-Fluorophenoxy)-7-azaspiro[3.5]non-7-yl]methyl-1H-pyrazin-2-one

The title compound (25 mg, 88% yield) was obtained in the same manner asExample 137 from 33 mg of7-(3-tert-butoxy-2-pyrazinylmethyl)-2-(2-fluorophenoxy)-7-azaspiro[3.5]nonane.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78 (4H, dt, J=15.2, 5.4 Hz), 2.02-2.07(2H, m), 2.40-2.70 (6H, m), 3.83 (2H, s), 4.71 (1H, quintet, J=6.8 Hz),6.78 (1H, td, J=8.2, 1.6 Hz), 6.88 (1H, tdd, J=7.8, 4.4, 1.6 Hz), 7.02(1H, tt, J=8.0, 1.2 Hz), 7.07 (1H, ddd, J=11.6, 8.0, 1.6 Hz), 7.91 (1H,d, J=2.8 Hz), 7.94 (1H, br s).

Example 2273-[4-[2-(2-Methylphenyl)ethyl]azepan-1-yl]methyl-1H-pyrazin-2-oneoxalate

3-[4-[2-(2-Methylphenyl)ethyl]azepan-1-yl]methyl-1H-pyrazin-2-one (67mg) was obtained in the same manner as Example 118 from 109 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-4-[2-(2-methylphenyl)ethyl]azepane,and was then converted to an oxalate by a ordinary method to obtain thetitle compound (71 mg, 61% yield, 2 steps).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.27-1.35 (1H, m), 1.39-1.45 (2H, m),1.56-1.64 (2H, m), 1.70-1.90 (4H, m), 2.23 (3H, br s), 2.51-2.55 (2H,m), 3.07-3.29 (4H, m), 4.17 (2H, s), 7.04-7.11 (4H, m), 7.35 (1H, d, J=4Hz), 7.48 (1H, d, J=4 Hz).

Example 228(E)-5-[4-[2-(2-Fluorophenyl)vinyl]piperidino]methyl-1H,3H-pyrimidine-2,4-dione

After dissolving 100 mg of (E)-4-[2-(2-fluorophenyl)vinyl]piperidine in3 ml of tetrahydrofuran, 116 mg of2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehyde, 0.05 ml ofacetic acid and 198 mg of sodium triacetoxyborohydride were added whilestirring, and the stirring was continued for 20 hours at roomtemperature. An additional 200 mg of sodium triacetoxyborohydride wasthen added and the mixture was stirred overnight at room temperature.Aqueous sodium carbonate solution was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent:tetrahydrofuran/methanol). Ethyl acetate was added and the mixture wasfiltered to obtain the title compound (90 mg, 38% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.32-1.44 (2H, m), 1.66-1.73 (2H, m),1.94-2.02 (2H, m), 2.07-2.18 (1H, m), 2.79-2.85 (2H, m), 3.11 (2H, s),6.35 (1H, dd, J=16.0, 6.4 Hz), 6.47 (1H, d, J=16.0 Hz), 7.12-7.19 (2H,m), 7.22-7.29 (2H, m), 7.57 (1H, dt, J=7.2, 1.6 Hz), 10.76 (1H, br s),11.04 (1H, br s).

Example 2294-[4-(2-Fluorophenoxymethyl)piperidino]methyl-2H-pyridazin-3-one

After dissolving 1.82 g of methyl 3-methoxypyridazine-4-carboxylate in50 ml of tetrahydrofuran, 11 ml of diisobutylaluminium hydride (1.01 M,toluene solution) was added dropwise while stirring at below −70° C. andthe stirring was continued for 1 hour. The temperature was raised to−45° C. and saturated aqueous ammonium chloride solution was added.After adding 1N hydrochloric acid to the reaction solution, extractionwas performed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate). The obtained product was dissolved in 3 ml of dichloromethane,and then 220 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride and288 mg of sodium triacetoxyborohydride were added while stirring on iceand the stirring was continued overnight at room temperature. A 1Nsodium hydroxide solution was added to the reaction mixture andextraction was performed with ethyl acetate. The organic layer waswashed with brine and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate). The obtained product was dissolved in 4 ml of ethanol, 1 ml of4N hydrogen chloride/ethyl acetate was added while stirring, and themixture was heated to reflux for 3 hours. The reaction solution wasallowed to cool, and then 1 ml of concentrated hydrochloric acid wasadded and the mixture was heated to reflux for 3 hours and then stirredat room temperature for 7 days. A 5N sodium hydroxide solution was addedto the reaction solution and extraction was performed with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. Diethyl ether was added and the insolubleportion was filtered out to obtain the title compound (13 mg, 0.4%yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.56 (2H, m), 1.84-1.97 (3H, m),2.16-2.24 (2H, m), 2.88-2.94 (2H, m), 3.51 (2H, d, J=1.2 Hz), 3.89 (2H,d, J=6.0 Hz), 6.86-6.92 (1H, m), 6.96 (1H, td, J=8.0, 1.6 Hz), 7.02-7.11(2H, m), 7.39 (1H, dt, J=4.0, 1.6 Hz), 7.80 (1H, d, J=4.0 Hz).

Example 2305-[4-(2-Fluorophenoxymethyl)piperidino]methyl-3H-pyrimidin-4-one

The title compound (116 mg, 81% yield) was obtained in the same manneras Example 137 from 167 mg of4-tert-butoxy-5-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrimidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.52 (2H, m), 1.84-1.96 (3H, m),2.11-2.20 (2H, m), 2.96-3.03 (2H, m), 3.47 (2H, s), 3.88 (2H, d, J=6.4Hz), 6.85-6.92 (1H, m), 6.95 (1H, dt, J=8.0, 1.6 Hz), 7.02-7.10 (2H, m),8.10 (1H, s), 8.19 (1H, s).

Example 2316-[2-[4-Hydroxy-4-(2-fluorophenoxymethyl)piperidino]ethyl]-1H-pyridin-2-one

The title compound (12 mg, 77% yield) was obtained in the same manner asExample 118 from 18 mg of1-[2-(6-tert-butoxypyridin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.81-1.94 (4H, m), 2.35 (1H, br s),2.31-2.59 (2H, m), 2.63-2.69 (2H, m), 2.74-2.80 (2H, m), 2.86-2.92 (2H,m), 3.93 (2H, s), 5.92 (1H, dd, J=6.8, 0.8 Hz), 6.38 (1H, dd, J=9.2, 0.8Hz), 6.90-7.01 (2H, m), 7.04-7.12 (2H, m), 7.27 (1H, dd, J=9.2, 6.8 Hz).

Example 2323-[2-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (23 mg, 77% yield) was obtained in the same manner asExample 137 from 36 mg of2-tert-butoxy-3-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.52-1.64 (2H, m), 1.93-2.06 (3H, m),2.26-2.36 (2H, m), 2.83-2.88 (2H, m), 3.07-3.13 (2H, m), 3.20-3.28 (2H,m), 3.90 (2H, d, J=6.4 Hz), 6.87-6.98 (2H, m), 7.03-7.11 (2H, m), 7.74(1H, brs), 7.78 (1H, br s).

Example 2336-[2-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

After dissolving 167 mg of2-tert-butoxy-6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazinein 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate wasadded and the mixture was allowed to stand at room temperature for 30minutes. Aqueous sodium carbonate solution was added to the reactionsolution and extraction was performed with dichloromethane. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.Diethyl ether was added to the residue and the mixture was filtered toobtain the title compound (113 mg, 79% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.56 (2H, m), 1.91-2.04 (3H, m),2.11-2.19 (2H, m), 2.61-2.66 (2H, m), 2.73-2.78 (2H, m), 3.08-3.15 (2H,m), 3.91 (2H, d, J=6.4 Hz), 6.86-6.93 (1H, m), 6.96 (1H, dt, J=8.4, 1.6Hz), 7.03-7.11 (2H, m), 7.12 (1H, s), 8.02 (1H, s).

Example 234(E)-6-[2-[4-[2-(2-Fluorophenyl)vinyl]piperidino]ethyl]-1H-pyrazin-2-one

The title compound (3 mg, 30% yield) was obtained in the same manner asExample 118 from 13 mg of(E)-2-tert-butoxy-6-[2-[4-[2-(2-fluorophenyl)vinyl]piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.62-1.75 (2H, m), 1.85-1.93 (2H, m),2.14-2.32 (3H, m), 2.61-2.66 (2H, m), 2.74-2.79 (2H, m), 3.07-3.14 (2H,m), 6.25 (1H, dd, J=16.0, 7.2 Hz), 6.58 (1H, d, J=16.0 Hz), 7.02 (1H,ddd, J=10.8, 8.0, 1.2 Hz), 7.09 (1H, dt, J=7.6, 1.2 Hz), 7.12 (1H, s),7.15-7.22 (1H, m), 7.45 (1H, dt, J=7.6, 1.6 Hz), 8.03 (1H, s).

Example 2356-[2-[4-(2-Chlorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (55 mg, 44% yield) was obtained in the same manner asExample 137 from 145 mg of2-tert-butoxy-6-[2-[4-(2-chlorophenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.59 (2H, m), 1.93-2.06 (3H, m),2.12-2.21 (2H, m), 2.61-2.66 (2H, m), 2.74-2.79 (2H, m), 3.09-3.16 (2H,m), 3.90 (2H, d, J=6.4 Hz), 6.87-6.94 (2H, m), 7.12 (1H, s), 7.22 (1H,dt, J=7.6, 1.6 Hz), 7.36 (1H, dd, J=7.6, 1.6 Hz), 8.02 (1H, s).

Example 2366-[2-[4-(2-Methylphenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (86 mg, 66% yield) was obtained in the same manner asExample 137 from 152 mg of2-tert-butoxy-6-[2-[4-(2-methylphenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.49-1.62 (2H, m), 1.88-2.01 (3H, m),2.12-2.20 (2H, m), 2.24 (3H, s), 2.61-2.66 (2H, m), 2.74-2.79 (2H, m),3.09-3.16 (2H, m), 3.86 (2H, d, J=6.0 Hz), 6.80 (1H, d, J=8.4 Hz), 6.86(1H, dt, J=7.6, 1.2 Hz), 7.12-7.18 (3H, m), 8.02 (1H, s).

Example 2376-[2-[4-[2-(2-Fluorophenyl)acetyl]piperidino]ethyl]-1H-pyrazin-2-one

After dissolving 1.00 g of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride in 8 ml of N,N-dimethylformamide, 643 mg of potassiumcarbonate and 899 mg of 2-tert-butoxy-6-vinylpyrazine were added whilestirring, and the stirring was continued for 64 hours at 100° C. Waterwas added to the reaction mixture and extraction was performed withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: n-hexane/ethyl acetate).Three milliliters of 4N hydrogen chloride/ethyl acetate was added to theobtained product and the mixture was stirred for 2.5 hours at roomtemperature. A 1N sodium hydroxide solution was added to the reactionsolution and extraction was performed with dichloromethane. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:chloroform/methanol/ammonia water) to obtain the title compound (27 mg,2% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.83-1.94 (2H, m), 1.96-2.04 (2H, m),2.19-2.28 (2H, m), 2.50-2.62 (3H, m), 2.71-2.76 (2H, m), 2.99-3.06 (2H,m), 3.80 (2H, s), 7.06 (1H, ddd, J=9.8, 8.0, 1.2 Hz), 7.09-7.14 (2H, m),7.18 (1H, td, J=8.0, 2.0 Hz), 7.24-7.30 (1H, m), 8.02 (1H, s).

Example 2386-[2-[4-(3-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (219 mg, 84% yield) was obtained in the same manneras Example 118 from 304 mg of2-tert-butoxy-6-[2-[4-(3-fluorophenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45-1.57 (2H, m), 1.84-1.99 (3H, m),2.10-2.18 (2H, m), 2.61-2.66 (2H, m), 2.74-2.79 (2H, m), 3.08-3.15 (2H,m), 3.83 (2H, d, J=6.4 Hz), 6.58-6.70 (3H, m), 7.12 (1H, s), 7.22 (1H,dt, J=8.0, 6.8 Hz), 8.02 (1H, s).

Example 2396-[2-[4-(2,4-Difluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (201 mg, 83% yield) was obtained in the same manneras Example 118 from 280 mg of2-tert-butoxy-6-[2-[4-(2,4-difluorophenoxymethyl)piperidino]ethyl]pyrazine.

H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.56 (2H, m), 1.88-2.02 (3H, m),2.10-2.19 (2H, m), 2.61-2.66 (2H, m), 2.73-2.79 (2H, m), 3.08-3.16 (2H,m), 3.87 (2H, d, J=6.4 Hz), 6.76-6.94 (3H, m), 7.12 (1H, s), 8.02 (1H,s).

Example 2406-[2-[4-(2-Methoxyphenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (192 mg, 56% yield) was obtained in the same manneras Example 118 from 305 mg of2-tert-butoxy-6-[2-[4-(2-methoxyphenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.56 (2H, m), 1.94-2.06 (3H, m),2.10-2.18 (2H, m), 2.61-2.66 (2H, m), 2.73-2.78 (2H, m), 3.07-3.14 (2H,m), 3.87 (3H, s), 3.89 (2H, d, J=6.4 Hz), 6.87-6.96 (4H, m), 7.13 (1H,s), 8.01 (1H, s).

Example 2416-[2-[4-(2,5-Difluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (178 mg, 88% yield) was obtained in the same manneras Example 118 from 236 mg of2-tert-butoxy-6-[2-[4-(2,5-difluorophenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.57 (2H, m), 1.90-2.03 (3H, m),2.11-2.21 (2H, m), 2.61-2.67 (2H, m), 2.73-2.81 (2H, m), 3.08-3.17 (2H,m), 3.87 (2H, d, J=6.4 Hz), 6.54-6.61 (1H, m), 6.65-6.72 (1H, m),6.96-7.04 (1H, m), 7.12 (1H, s), 8.01 (1H, s).

Example 2426-[2-[4-(2,3-Difluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (124 mg, 85% yield) was obtained in the same manneras Example 118 from 172 mg of2-tert-butoxy-6-[2-[4-(2,3-difluorophenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.56 (2H, m), 1.91-2.03 (3H, m),2.12-2.20 (2H, m), 2.61-2.67 (2H, m), 2.74-2.80 (2H, m), 3.09-3.16 (2H,m), 3.91 (2H, d, J=6.4 Hz), 6.70-6.81 (2H, m), 6.98 (1H, ddt, J=8.4,6.0, 2.4 Hz), 7.13 (1H, s), 8.02 (1H, s).

Example 2436-[2-[4-[2-(2-Fluorophenyl)ethyl]piperidino]ethyl]-1H-pyrazin-2-one

The title compound (240 mg, 91% yield) was obtained in the same manneras Example 118 from 309 mg of2-tert-butoxy-6-[2-[4-[2-(2-fluorophenyl)ethyl]piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.28-1.47 (3H, m), 1.57-1.64 (2H, m),1.80-1.88 (2H, m), 2.02-2.11 (2H, m), 2.59-2.75 (6H, m), 3.02-3.09 (2H,m), 6.97-7.03 (1H, m), 7.06 (1H, dt, J=7.2, 1.2 Hz), 7.12 (1H, s),7.13-7.21 (2H, m), 8.01 (1H, s).

Example 2446-[2-[4-[(2-Fluorophenyl)ethynyl]piperidino]ethyl]-1H-pyrazin-2-one

The title compound (36 mg, 74% yield) was obtained in the same manner asExample 118 from 59 mg of2-tert-butoxy-6-[2-[4-[(2-fluorophenyl)ethynyl]piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.88-1.97 (2H, m), 2.01-2.10 (2H, m),2.52 (1H, br s), 2.61-2.67 (2H, m), 2.75-2.80 (2H, m), 2.86 (4H, br s),7.03-7.11 (2H, m), 7.13 (1H, s), 7.24-7.30 (1H, m), 7.41 (1H, dt, J=7.2,1.6 Hz), 8.03 (1H, s).

Example 245 6-[2-[4-(Phenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

After dissolving 471 mg of 2-tert-butoxy-6-vinylpyrazine and 505 mg of4-(phenoxymethyl)piperidine in 10 ml of ethanol, the mixture was stirredfor 4 days at 80° C. The reaction solution was concentrated underreduced pressure and the residue was purified by NH silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain2-tert-butoxy-6-[2-(4-phenoxymethylpiperidino)ethyl]pyrazine.

This was dissolved in 3 ml of ethyl acetate, 3 ml of 4N hydrogenchloride/ethyl acetate was added, and the mixture was allowed to standat room temperature for 1.5 hours. Aqueous sodium bicarbonate solutionwas added to the reaction solution and extraction was performed withethyl acetate. The organic layer was washed with water and saturatedbrine in that order and dried over anhydrous magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. Diethyl ether wasadded to the residue and the mixture was filtered to obtain the titlecompound (273 mg, 94% yield, 2 steps).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.58 (2H, m), 1.85-2.00 (3H, m),2.11-2.19 (2H, m), 2.61-2.66 (2H, m), 2.74-2.78 (2H, m), 3.08-3.15 (2H,m), 3.85 (2H, d, J=6.4 Hz), 6.88-6.97 (3H, m), 7.12 (1H, s), 7.26-7.32(2H, m), 8.02 (1H, s).

Example 2466-[2-[4-(4-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (242 mg, 30% yield) was obtained in the same manneras Example 245 from 436 mg of 2-tert-butoxy-6-vinylpyrazine and 512 mgof 4-(4-fluorophenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45-1.57 (2H, m), 1.83-1.98 (3H, m),2.10-2.18 (2H, m), 2.61-2.66 (2H, m), 2.73-2.78 (2H, m), 3.08-3.15 (2H,m), 3.81 (2H, d, J=6.4 Hz), 6.80-6.86 (2H, m), 6.94-7.01 (2H, m), 7.12(1H, s), 8.02 (1H, s).

Example 2476-[2-[4-(2,6-Difluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one

The title compound (242 mg, 89% yield) was obtained in the same manneras Example 118 from 316 mg of2-tert-butoxy-6-[2-[4-(2,6-difluorophenoxymethyl)piperidino]ethyl]pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.55 (2H, m), 1.85-2.03 (3H, m),2.10-2.18 (2H, m), 2.61-2.66 (2H, m), 2.73-2.78 (2H, m), 3.07-3.14 (2H,m), 4.00 (2H, d, J=6.4 Hz), 6.85-6.99 (3H, m), 7.12 (1H, s), 8.01 (1H,s).

Example 2486-[2-[4-[2-(2-Fluorophenyl)-2-oxoethyl]piperidino]ethyl]-1H-pyrazin-2-one

The title compound (36 mg, 45% yield) was obtained in the same manner asExample 118 from 89 mg of2-[1-[2-(6-tert-butoxy-2-pyrazinyl)ethyl]-piperidin-4-yl]-1-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.54 (2H, m), 1.84-1.93 (2H, m),2.10-2.22 (3H, m), 2.60-2.66 (2H, m), 2.73-2.78 (2H, m), 2.93-2.98 (2H,m), 3.04-3.53 (2H, m), 7.13 (1H, s), 7.28-7.32 (1H, m), 7.45-7.51 (1H,m), 7.63-7.68 (1H, m), 7.74-7.7.8 (1H, m), 8.03 (1H, s).

Example 2496-[2-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-1-methyl-1H-pyrazin-2-one

After dissolving 330 mg of6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one in 3ml of N,N-dimethylformamide, 44 mg of sodium hydride (70% suspension inoil) was added while stirring, and the stirring was continued for 1 hourat room temperature. Next, 0.068 ml of methyl iodide was added and themixture was stirred overnight at room temperature. Water was added tothe reaction solution and extraction was performed with ethyl acetate.The organic layer was washed with water and saturated brine in thatorder and dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified by NHsilica gel column chromatography (solvent: ethyl acetate). Diethyl etherwas added and the mixture was filtered to obtain the title compound (116mg, 34% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35-1.48 (2H, m), 1.83-1.94 (3H, m),2.07-2.16 (2H, m), 2.63-2.68 (2H, m), 2.78-2.84 (2H, m), 2.96-3.03 (2H,m), 3.52 (3H, s), 3.87 (2H, d, J=6.4 Hz), 6.86-6.92 (1H, m), 6.96 (1H,dt, J=8.8, 1.6 Hz), 7.02-7.10 (2H, m), 7.23 (1H, s), 8.03 (1H, s).

Example 2503-(2-Fluorobenzyl)-8-(2-oxo-1,2-dihydro-3-pyridylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one

The title compound (6 mg, 48% yield) was obtained in the same manner asExample 130 from 13 mg of3-(2-fluorobenzyl)-8-(2-methoxypyridin-3-yl)methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.73-1.80 (2H, m), 1.90-1.95 (2H, m),2.55-2.68 (4H, m), 3.20 (2H, s), 3.49 (2H, s), 4.50 (2H, s), 6.29 (1H,t, J=2.6 Hz), 7.07 (1H, t, J=9.2 Hz), 7.15 (1H, t, J=7.4 Hz), 7.28-7.36(3H, m), 7.50 (1H, d, J=6.4 Hz).

Example 2513-[4-Hydroxy-4-(2-methyl-5-phenylpyrrol-1-yl)methyl-piperidino]methyl-1H-pyridin-2-one

After dissolving 35 mg of4-hydroxy-4-(2-phenyl-5-methylpyrrol-1-yl)methyl-piperidine in 5 ml ofdichloromethane, 16 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde and0.02 ml of acetic acid were added and the mixture was stirred for 20minutes at room temperature. Next, 41 mg of sodium triacetoxyborohydridewas added and the mixture was stirred overnight at room temperature.Saturated aqueous sodium bicarbonate solution was added to the reactionmixture and extraction was performed with ethyl acetate and chloroform.After drying the organic layer over magnesium sulfate, the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby NH silica gel column chromatography to obtain the title compound (19mg, 39% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.25-1.51 (6H, m), 2.18-2.30 (2H, m),2.39 (3H, s), 2.45-2.55 (2H, m), 3.38 (2H, s), 6.00 (1H, d, J=3.6 Hz),6.12 (1H, d, J=3.6 Hz), 6.25-6.33 (1H, m), 7.26-7.44 (7H, m).

Example 2523-[4-Hydroxy-4-(2-methylphenoxymethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (16 mg, 31% yield) was obtained in the same manner asExample 122 from 40 mg of 4-hydroxy-4-(2-methylphenoxymethyl)piperidinehydrochloride and 19 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.85 (4H, m), 2.25 (3H, s),2.55-2.63 (2H, m), 2.71-2.77 (2H, m), 3.55 (2H, s), 3.84 (2H, s), 6.33(1H, t, J=6.6 Hz), 6.81 (1H, d, J=8.0 Hz), 6.89-6.91 (1H, m), 7.14-7.18(2H, m), 7.36 (1H, dd, J=6.4, 2.0 Hz), 7.55-7.58 (1H, m).

Example 2533-[4-Hydroxy-4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (3 mg, 16% yield) was obtained in the same manner asExample 122 from 40 mg of 4-(2-fluorophenoxymethyl)-4-hydroxypiperidinehydrochloride and 19 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.85 (4H, m), 2.55-2.63 (2H, m),2.71-2.77 (2H, m), 3.55 (2H, s), 3.89 (2H, s), 6.33 (1H, t, J=6.8 Hz),6.89-6.95 (1H, m), 6.97 (1H, td, J=8.4, 1.6 Hz), 7.03-7.11 (2H, m),7.34-7.38 (1H, m), 7.54-7.57 (1H, m).

Example 2545-Chloro-3-[4-hydroxy-4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (18 mg, 32% yield) was obtained in the same manner asExample 122 from 40 mg of 4-(2-fluorophenoxymethyl)-4-hydroxypiperidinehydrochloride and 29 mg of5-chloro-2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.75-1.90 (4H, m), 2.63 (2H, td, J=11.4,3.0 Hz), 2.73-2.80 (2H, m), 3.59 (2H, s), 3.89 (2H, s), 6.90-6.97 (1H,m), 6.98 (1H, dd, J=12.2, 1.8 Hz), 7.04-7.07 (1H, m), 7.08-7.12 (1H, m),7.44 (1H, d, J=2.4 Hz), 7.69 (1H, br s).

Example 2553-[4-(Ethoxycarbonyl)-4-(2-phenylethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (17 mg, 88% yield) was obtained in the same manner asExample 130 from 20 mg of ethyl1-(2-methoxy-3-pyridinylmethyl)-4-(2-phenylethyl)piperidine-4-carboxylate.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.29 (3H, t, J=7.2 Hz), 1.43-1.63 (2H,m), 1.81-1.86 (2H, m), 2.20-2.28 (4H, m), 2.49-2.54 (2H, m), 2.75-2.82(2H, m), 3.46 (2H, s), 4.19 (2H, q, J=7.2 Hz), 6.32 (1H, t, J=6.6 Hz),7.14 (1H, d, J=6.8 Hz), 7.15-7.20 (1H, m), 7.25-7.29 (3H, m), 7.32-7.36(1H, m), 7.52-7.58 (1H, m).

Example 2563-[4-Hydroxymethyl-4-(2-phenylethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (4 mg, 32% yield) was obtained in the same manner asExample 130 from 23 mg of1-(2-methoxypyridin-3-yl)methyl-4-(2-phenylethyl)piperidine-4-methanol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.56-1.61 (4H, m), 1.69-1.74 (2H, m),2.50-2.60 (6H, m), 3.50 (2H, s), 3.56 (2H, s), 6.30-6.38 (1H, m),7.17-7.21 (3H, m), 7.26-7.31 (3H, m), 7.48-7.53 (1H, m).

Example 2573-[4-(2-Fluorophenoxymethyl)-4-(2-phenylethyl)piperidino]methyl-1H-pyridin-2-one

The title compound (2 mg, 41% yield) was obtained in the same manner asExample 130 from 5 mg of3-[4-(2-fluorophenoxymethyl)-4-(2-phenylethyl)piperidino]methyl-2-methoxypyridine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.53-1.94 (6H, m), 2.32-2.45 (2H, m),2.59-2.63 (2H, m), 3.15-3.40 (2H, m), 4.16 (2H, s), 4.39 (2H, s),6.45-6.55 (1H, m), 7.11-7.55 (11H, m).

Example 2583-[4-Hydroxy-4-[(2-fluorophenyl)ethynyl]piperidino]methyl-1H-pyridin-2-one

After dissolving 1.4 g of1-(tert-butoxycarbonyl)-4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidinein 20 ml of ethyl acetate, 10 ml of 4N hydrogen chloride/ethyl acetatewas added and the mixture was stirred overnight at room temperature. Thesolvent was distilled off under reduced pressure to obtain 1.28 g of4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidine hydrochloride.

After then adding 253 mg of the4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidine hydrochloride to 10 mlof dichloromethane, 158 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehydewas added and the mixture was stirred for 10 minutes at roomtemperature. Next, 315 mg of sodium triacetoxyborohydride was added andthe mixture was stirred overnight at room temperature. Saturated aqueoussodium bicarbonate solution was added to the reaction mixture andextraction was performed with ethyl acetate. After drying the organiclayer over magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was purified by NH silica gel columnchromatography to obtain the title compound (32 mg, 10% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.99 (2H, ddd, J=12.8, 9.2, 3.6 Hz),2.04-2.13 (2H, m), 2.56-2.62 (2H, m), 2.80-2.84 (2H, m), 3.54 (2H, s),6.32 (1H, t, J=6.6 Hz), 7.04-7.11 (2H, m), 7.26-7.33 (1H, m), 7.35 (1H,dd, J=6.4, 2.0 Hz), 7.38-7.43 (1H, m), 7.57-7.60 (1H, m).

Example 2593-[4-Hydroxy-4-[(2-methylphenyl)ethynyl]piperidino]methyl-1H-pyridin-2-one

The title compound (18 mg, 21% yield) was obtained in the same manner asExample 122 from 66 mg of4-hydroxy-4-[(2-methylphenyl)ethynyl]piperidine hydrochloride and 42 mgof 2-oxo-1,2-dihydropyridine-3-carboxaldehyde.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.95-2.02 (2H, m), 2.04-2.11 (2H, m),2.42 (3H, s), 2.53-2.62 (2H, m), 2.79-2.85 (2H, m), 3.54 (2H, s), 6.31(1H, t, J=6.6 Hz), 7.10-7.14 (1H, m), 7.18-7.24 (2H, m), 7.34 (1H, d,J=6.4 Hz), 7.38 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=6.8 Hz).

Example 2602-Amino-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine

After adding 4 ml of n-butyllithium (2.46 M, n-hexane solution) to asolution of 1.384 g of 2,2,6,6-tetramethylpiperidine in tetrahydrofuran(15 ml) at −20° C. under a nitrogen atmosphere, the mixture was stirredfor 30 minutes while cooling on ice. The reaction mixture was cooled to−70° C., and then a solution of 800 mg of2-(tert-butoxycarbonylamino)pyrazine in tetrahydrofuran (3 ml) was addeddropwise, the mixture was stirred for 1 hour, 3 ml ofN,N-dimethylformaldehyde was added, and stirring was continued for 30minutes. After removing the cooling bath and stirring for 30 minutes,water was added and extraction was performed with ethyl acetate. Theextract was dried and concentrated and then purified by silica gelcolumn chromatography (solvent: ethyl acetate/n-hexane) to obtain 72 mgof crude 2-(tert-butoxycarbonylamino)pyrazine-3-carboxaldehyde.

This was dissolved in 3 ml of dichloromethane, and then 79 mg of4-(2-fluorophenoxymethyl)piperidine hydrochloride and 102 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. A 2N sodium hydroxide solution was added to thereaction mixture, extraction was performed with ethyl acetate and theextract was concentrated under reduced pressure.

The residue was dissolved in 1 ml of dichloromethane, 1 ml oftrifluoroacetic acid was added while cooling on ice and the mixture wasstirred for 1 hour. The reaction solution was concentrated anddistributed in ethyl acetate/water, and the organic layer was washedwith water and dried. After concentration under reduced pressure, theresidue was purified by NH-silica gel column chromatography (solvent:ethyl acetate/n-hexane) to obtain the title compound (8 mg, 8% yield, 3steps).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.45 (2H, m), 1.86-1.96 (3H, m),2.11-2.17 (2H, m), 2.87 (2H, d, J=11.6 Hz), 3.69 (2H, s), 3.88 (2H, d,J=6.0 Hz), 5.91 (2H, br s), 6.86-6.97 (2H, m), 7.03-7.10 (2H, m), 7.79(1H, d, J=3.0 Hz), 7.90 (1H, d, J=3.0 Hz).

Example 2612-tert-Butylthio-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (205 mg, 57% yield) was obtained in the same manneras Example 1 from 180 mg of 2-(tert-butylthio)pyrazine-3-carboxaldehydeand 248 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.52 (2H, m), 1.59 (9H, s),1.79-1.94 (3H, m), 2.12-2.20 (2H, m), 2.95-3.02 (2H, m), 3.64 (2H, s),3.85 (2H, d, J=6.4 Hz), 6.84-6.90 (1H, m), 6.94 (1H, dt, J=8.8, 1.6 Hz),7.01-7.09 (2H, m), 8.21 (1H, d, J=2.8 Hz), 8.23 (1H, d, J=2.8 Hz).

Example 2623-[4-(2-Fluorophenoxymethyl)piperidino]methyl-1H-pyrazine-2-thione

The title compound (54 mg, 31% yield) was obtained in the same manner asExample 130 from 205 mg of2-tert-butylthio-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.73-1.86 (2H, m), 2.11-2.24 (3H, m),2.80-2.90 (2H, m), 3.43-3.50 (2H, m), 3.94 (2H, d, J=6.0 Hz), 4.17 (2H,s), 6.91-6.97 (2H, m), 7.03-7.12 (2H, m), 7.85 (1H, d, J=2.8 Hz), 8.23(1H, br s).

Example 2632-tert-Butoxy-3-[4-(2-fluorobenzylthio)piperidino]methyl-pyrazine

The title compound (224 mg, 66% yield) was obtained in the same manneras Example 1 from 187 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and227 mg of 4-(2-fluorobenzylthio)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.63-1.75 (2H, m),1.90-1.98 (2H, m), 2.16-2.25 (2H, m), 2.55-2.64 (1H, m), 2.89-2.97 (2H,m), 3.61 (2H, s), 3.76 (2H, s), 7.01 (1H, ddd, J=9.8, 8.0, 1.2 Hz), 7.08(1H, td, J=8.0, 1.2 Hz), 7.17-7.24 (1H, m), 7.34 (1H, td, J=8.0, 2.0Hz), 7.90 (1H, d, J=2.8 Hz), 8.01 (1H, d, J=2.8 Hz).

Example 2642-tert-Butoxy-3-[4-(2-fluorobenzylsulfonyl)piperidino]methyl-pyrazine

The title compound (168 mg, 59% yield) was obtained in the same manneras Example 1 from 147 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 4-(2-fluorobenzylsulfonyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.90-2.18 (6H, m),2.72-2.81 (1H, m), 3.10-3.18 (2H, m), 3.63 (2H, s), 4.28 (2H, s), 7.11(1H, ddd, J=9.8, 8.0, 1.2 Hz), 7.19 (1H, td, J=8.0, 1.2 Hz), 7.34-7.40(1H, m), 7.50 (1H, td, J=8.0, 2.0 Hz), 7.93 (1H, d, J=2.8 Hz), 8.01 (1H,d, J=2.8 Hz).

Example 2652-tert-Butoxy-3-[4-[(2-fluorophenylthio)methyl]piperidino]methyl-pyrazine

The title compound (70 mg, 90% yield) was obtained in the same manner asExample 1 from 43 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 52 mgof 4-[(2-fluorophenylthio)methyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.62 (3H, m), 1.58 (9H, s),1.80-1.88 (2H, m), 2.03-2.12 (2H, m), 2.82 (1H, d, J=6.8 Hz), 2.94-3.01(2H, m), 3.61 (2H, s), 6.99-7.09 (2H, m), 7.14-7.20 (1H, m), 7.32 (1H,td, J=8.0, 2.0 Hz), 7.90 (1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 2662-tert-Butoxy-3-[4-[(2-fluorophenylsulfinyl)methyl]piperidino]methyl-pyrazine

4-[(2-Fluorophenylsulfinyl)methyl]piperidine (49 mg) was obtained in thesame manner as Production Example 116 from 68 mg of1-(tert-butoxycarbonyl)-4-[(2-fluorophenylsulfinyl)methyl]piperidine.

After then dissolving 44 mg of 3-tert-butoxypyrazine-2-carboxaldehydeand 49 mg of the 4-[(2-fluorophenylsulfinyl)methyl]piperidine in 2 ml ofdichloromethane, 65 mg of sodium triacetoxyborohydride was added and themixture was stirred overnight at room temperature. A 1N sodium hydroxidesolution was added to the reaction mixture and extraction was performedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (solvent: ethyl acetate/methanol) to obtainthe title compound (43 mg, 52% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.76 (3H, m), 1.60 (9H, s),1.98-2.24 (4H, m), 2.75-2.84 (2H, m), 2.94-3.06 (2H, m), 3.63 (2H, s),7.09 (1H, ddd, J=9.6, 8.0, 1.2 Hz), 7.37 (1H, td, J=8.0, 1.2 Hz),7.43-7.50 (1H, m), 7.83 (1H, td, J=8.0, 2.0 Hz), 7.91 (1H, d, J=2.8 Hz),8.02 (1H, d, J=2.8 Hz).

Example 2672-tert-Butoxy-3-[4-[(2-fluorophenylsulfonyl)methyl]piperidino]methyl-pyrazine

The title compound (48 mg, 93% yield) was obtained in the same manner asExample 1 from 26 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 36 mgof 4-[(2-fluorophenylsulfonyl)methyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.62 (2H, m), 1.57 (9H, s),1.81-1.89 (2H, m), 1.98-2.18 (3H, m), 2.89-2.97 (2H, m), 3.22 (2H, d,J=6.4 Hz), 3.59 (2H, s), 7.19-7.26 (1H, m), 7.33 (1H, td, J=8.0, 1.2Hz), 7.60-7.66 (1H, m), 7.89-7.96 (2H, m), 8.01 (1H, d, J=2.8 Hz).

Example 2685-tert-Butoxy-3-chloro-2-[4-(2-fluorobenzyloxy)piperidino]methyl-pyrazine

The title compound (137 mg, 49% yield) was obtained in the same manneras Example 1 from 146 mg of5-tert-butoxy-3-chloropyrazine-2-carboxaldehyde and 201 mg of4-(2-fluorobenzyloxy)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.51 (2H, m), 1.60 (9H, s),1.81-1.94 (3H, m), 2.14-2.22 (2H, m), 2.97-3.03 (2H, m), 3.70 (2H, s),3.84 (2H, d, J=6.0 Hz), 6.83-6.88 (1H, m), 6.89-6.95 (1H, m), 6.99-7.08(2H, m), 8.01 (1H, s).

Example 2692-tert-Butoxy-3-[3-[2-(2-fluorophenyl)ethyl]morpholin-1-yl]methyl-pyrazine

After dissolving 180 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and251 mg of 3-[2-(2-fluorophenyl)ethyl]morpholine in 5 ml oftetrahydrofuran, 0.07 ml of acetic acid and 318 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. Aqueous sodium carbonate solution was added to thereaction mixture and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (329 mg,88% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.62-1.71 (1H, m),1.72-1.82 (1H, m), 2.04 (1H, t, J=11.2 Hz), 2.33 (1H, dt, J=11.2, 3.6Hz), 2.63-2.72 (1H, m), 2.76-2.86 (3H, m), 3.50-3.58 (1H, m), 3.61 (1H,d, J=14.0 Hz), 3.65 (1H, d, J=14.0 Hz), 3.71 (1H, dt, J=11.2, 2.4 Hz),3.84-3.89 (1H, m), 6.94-7.04 (2H, m), 7.10-7.19 (2H, m), 7.92 (1H, d,J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 270(E)-2-tert-Butoxy-3-[3-[2-(2-fluorophenyl)vinyl]morpholin-1-yl]methyl-pyrazine

The title compound (178 mg, 69% yield) was obtained in the same manneras Example 1 from 126 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and170 mg of (E)-3-[2-(2-fluorophenyl)vinyl]morpholine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 2.19 (1H, dt, J=11.2, 10.4Hz), 2.39 (1H, dt, J=11.2, 3.2 Hz), 2.80-2.85 (1H, m), 2.95-3.00 (1H,m), 3.67 (2H, s), 3.83 (1H, dt, J=11.2, 2.4 Hz), 3.94 (1H, ddd, J=11.2,3.2, 1.2 Hz), 4.24-4.30 (1H, m), 6.23 (1H, dd, J=16.0, 5.6 Hz), 6.77(1H, dd, J=16.0, 1.2 Hz), 7.00 (1H, ddd, J=10.8, 8.4, 1.2 Hz), 7.06 (1H,dt, J=7.6, 1.2 Hz), 7.15-7.21 (1H, m), 7.40 (1H, dt, J=7.6, 2.0 Hz),7.93 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 2712-tert-Butoxy-3-[3-(2-fluorophenoxymethyl)morpholin-1-yl]methyl-pyrazine

The title compound (258 mg, 83% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and248 mg of 3-(2-fluorophenoxymethyl)morpholine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 2.27 (1H, dt, J=11.2, 5.6Hz), 2.39 (1H, dt, J=11.2, 3.6 Hz), 2.78-2.84 (1H, m), 3.01-3.06 (1H,m), 3.69 (2H, s), 3.79 (1H, dt, J=11.2, 2.4 Hz), 3.88-3.93 (1H, m),3.98-4.10 (3H, m), 6.85-6.91 (1H, m), 6.93-7.07 (3H, m), 7.93 (1H, d,J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 2721-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(methylthio)phenyl]ethanone

The title compound (196 mg, 83% yield) was obtained in the same manneras Example 1 from 115 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and169 mg of 2-[2-(methylthio)phenyl]-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.74-1.92 (4H, m),2.12-2.22 (2H, m), 2.40-2.50 (1H, m), 2.41 (3H, s), 2.98-3.05 (2H, m),3.63 (2H, s), 3.88 (2H, s), 7.06-7.15 (2H, m), 7.21-7.28 (2H, m), 7.91(1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 2731-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone

After suspending 200 mg of1-(piperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone hydrochloridein 2 ml of dichloromethane, a solution of 140 mg of3-tert-butoxypyrazine-2-carboxaldehyde in dichloromethane (2 ml) and 207mg of sodium triacetoxyborohydride were added while stirring, and thestirring was continued overnight at room temperature. A 1N sodiumhydroxide solution was added to the reaction mixture and extraction wasperformed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (249 mg, 88% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.74-1.91 (4H, m),2.14-2.22 (2H, m), 2.39-2.48 (1H, m), 3.00-3.07 (2H, m), 3.64 (2H, s),3.95 (2H, d, J=1.2 Hz), 7.21 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz),7.49 (1H, t, J=7.6 Hz), 7.63 (1H, d, J=7.6 Hz), 7.92 (1H, d, J=2.8 Hz),8.03 (1H, d, J=2.8 Hz).

Example 2741-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(trifluoromethoxy)phenyl]ethanone

The title compound (266 mg, 95% yield) was obtained in the same manneras Example 1 from 133 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 1-(piperidin-4-yl)-2-[2-(trifluoromethoxy)phenyl]ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.74-1.90 (4H, m),2.14-2.22 (2H, m), 2.38-2.47 (1H, m), 2.99-3.06 (2H, m), 3.63 (2H, s),3.80 (2H, s), 7.18-7.32 (4H, m), 7.91 (1H, d, J=2.8 Hz), 8.02 (1H, d,J=2.8 Hz)

Example 2753-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-6-methyl-3,4-dihydropyrido[2,3-e][1,3]oxazin-2-one

The title compound (37 mg, 56% yield) was obtained in the same manner asExample 1 from 37 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 48 mgof 6-methyl-3-(piperidin-4-yl)-3,4-dihydropyrido[2,3-e][1,3]oxazin-2-onehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.74-1.80 (2H, m),1.90-2.02 (2H, m), 2.27-2.35 (2H, m), 2.51 (3H, s), 2.97-3.14 (2H, m),3.67 (2H, s), 4.23-4.32 (1H, m), 4.44 (2H, s), 7.05 (1H, d, J=8.0 Hz),7.20 (1H, d, J=8.0 Hz), 7.93 (1H, d, J=2.8 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 2762-[1-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-3-methoxypyrazine

After dissolving 1.09 g of 4-(2-fluorophenoxymethyl)piperidine in 15 mlof methanol, 1.53 ml of titanium (IV) tetraisopropoxide and 400 mg of2-acetyl-3-methoxypyrazine [CAS No. 56343-40-9] were added and themixture was stirred overnight at room temperature. The reaction solutionwas cooled on ice, 148 mg of sodium borohydride was added and themixture was stirred for 5 hours at room temperature. Water and ethylacetate were added to the reaction solution and the mixture was filteredwith celite. The filtrate was extracted with ethyl acetate and theextract was washed with saturated brine and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by NH silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (100 mg,11% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.30-1.51 (2H, m), 1.40 (3H, d, J=6.8Hz), 1.70-1.88 (3H, m), 2.03-2.12 (2H, m), 2.87-2.94 (1H, m), 3.16-3.23(1H, m), 3.82 (2H, d, J=6.4 Hz), 3.96 (3H, s), 4.15 (1H, q, J=6.8 Hz),6.82-6.94 (2H, m), 6.98-7.07 (2H, m), 7.95 (1H, d, J=2.8 Hz), 8.13 (1H,d, J=2.8 Hz).

Example 2771-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-ethoxyphenyl)ethanone

The title compound (264 mg, 91% yield) was obtained in the same manneras Example 1 from 152 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 2-(2-ethoxyphenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35 (3H, t, J=7.0 Hz), 1.59 (9H, s),1.72-1.88 (4H, m), 2.11-2.19 (2H, m), 2.38-2.47 (1H, m), 2.97-3.04 (2H,m), 3.62 (2H, s), 3.70 (2H, s), 3.99 (2H, t, J=7.0 Hz), 6.82 (1H, dd,J=7.6, 1.2 Hz), 6.87 (1H, td, J=7.6, 1.2 Hz), 7.08 (1H, dd, J=7.6, 1.6Hz), 7.20 (1H, td, J=7.6, 1.6 Hz), 7.91 (1H, d, J=2.8 Hz), 8.02 (1H, d,J=2.8 Hz).

Example 2781-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-n-propoxyphenyl)ethanone

The title compound (276 mg, 97% yield) was obtained in the same manneras Example 1 from 145 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 1-(piperidin-4-yl)-2-(2-n-propoxyphenyl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.00 (3H, t, J=7.4 Hz), 1.59 (9H, s),1.70-1.87 (6H, m), 2.10-2.18 (2H, m), 2.37-2.47 (1H, m), 2.96-3.04 (2H,m), 3.62 (2H, s), 3.71 (2H, s), 3.88 (2H, t, J=6.6 Hz), 6.82 (1H, dd,J=7.6, 1.2 Hz), 6.87 (1H, td, J=7.6, 1.2 Hz), 7.08 (1H, dd, J=7.6, 1.6Hz), 7.20 (1H, td, J=7.6, 1.6 Hz), 7.91 (1H, d, J=2.8 Hz), 8.02 (1H, d,J=2.8 Hz).

Example 2791-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)propanone

The title compound (300 mg, 86% yield) was obtained in the same manneras Example 21 from 189 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and206 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)propanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.35 (3H, d, J=7.0 Hz), 1.47-1.86 (4H,m), 1.57 (9H, s), 1.98-2.14 (2H, m), 2.30-2.40 (1H, m), 2.88-3.01 (2H,m), 3.58 (2H, s), 4.26 (1H, q, J=7.0 Hz), 7.04 (1H, ddd, J=9.6, 7.6, 1.2Hz), 7.09 (1H, dd, J=7.6, 1.2 Hz), 7.15 (1H, td, J=7.6, 2.0 Hz),7.18-7.26 (1H, m), 7.89 (1H, d, J=2.8 Hz), 8.00 (1H, d, J=2.8 Hz).

Example 2801-[1-[1-(3-Methoxy-2-pyrazinyl)ethyl]piperidin-4-yl]-2-(2-fluorophenyl)ethanone

After dissolving 1.012 g of triethylamine in 10 ml of ethanol, 2.575 gof 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride, 10 ml ofethanol, 2.951 ml of titanium (IV) tetraisopropoxide and 760 mg of2-acetyl-3-methoxypyrazine were added in that order and the mixture wasstirred for 5 hours and 20 minutes at room temperature. Next, 1.59 g ofsodium triacetoxyborohydride was added to the reaction mixture and themixture was stirred overnight at room temperature. A sodium carbonatesolution and ethyl acetate were added to the reaction mixture and themixture was filtered with celite. The filtrate was extracted with ethylacetate, and the extract was washed with water and saturated brine andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and then the residue was dissolved in ethylacetate and filtered with silica gel. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (solvent: n-hexane/ethyl acetate) to obtain thetitle compound (169 mg, 9% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38 (3H, d, J=6.8 Hz), 1.63-1.88 (4H,m), 2.04-2.18 (2H, m), 2.32-2.41 (1H, m), 2.90-2.97 (1H, m), 3.10-3.16(1H, m), 3.74 (2H, d, J=0.8 Hz), 3.95 (3H, s), 4.16 (1H, q, J=6.8 Hz),6.98-7.15 (3H, m), 7.19-7.26 (1H, m), 7.95 (1H, d, J=2.8 Hz), 8.11 (1H,d, J=2.8 Hz).

Example 281cis-1-(3-tert-Butoxy-2-pyrazinylmethyl)-3-(2-fluorophenoxymethyl)piperidin-4-ol

The title compound (198 mg, 75% yield) was obtained in the same manneras Example 269 from 122 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and153 mg of cis-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.73-1.82 (1H, m),1.85-1.94 (1H, m), 2.31-2.39 (1H, m), 2.57-2.76 (4H, m), 3.65 (1H, d,J=14.0 Hz), 3.70 (1H, d, J=14.0 Hz), 4.05-4.22 (3H, m), 6.85-6.92 (1H,m), 6.95 (1H, dt, J=8.4, 1.6 Hz), 7.00-7.08 (2H, m), 7.91 (1H, d, J=2.8Hz), 8.00 (1H, d, J=2.8 Hz).

Example 282trans-1-(3-tert-Butoxy-2-pyrazinylmethyl)-3-(2-fluorophenoxymethyl)piperidin-4-ol

The title compound (149 mg, 78% yield) was obtained in the same manneras Example 269 from 88 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and110 mg of trans-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.68-1.79 (1H, m),1.94-2.00 (1H, m), 2.08-2.26 (3H, m), 2.96-3.03 (1H, m), 3.07-3.13 (1H,m), 3.58-3.71 (3H, m), 4.04-4.14 (2H, m), 6.85-6.91 (1H, m), 6.95 (1H,dt, J=8.4, 1.6 Hz), 7.00-7.08 (2H, m), 7.92 (1H, d, J=2.8 Hz), 8.02 (1H,d, J=2.8 Hz).

Example 2831-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(1-naphthyl)ethanone

The title compound (126 mg, 78% yield) was obtained in the same manneras Example 1 from 149 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 2-(1-naphthyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.76-1.87 (4H, m),2.06-2.15 (2H, m), 2.42-2.51 (1H, m), 2.95-3.02 (2H, m), 3.60 (2H, s),4.16 (2H, s), 7.32 (1H, d, J=6.8 Hz), 7.39-7.51 (3H, m), 7.75-7.87 (3H,m), 7.90 (1H, d, J=2.8 Hz), 8.01 (1H, d, J=2.8 Hz).

Example 2843-[4-(2-Fluorophenoxymethyl)piperidino]methyl-2-methoxy-5-methylpyrazine

The title compound (126 mg, 78% yield) was obtained in the same manneras Example 1 from 149 mg of 3-methoxy-6-methylpyrazine-2-carboxaldehydeand 200 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.52 (2H, m), 1.80-1.92 (3H, m),2.15 (2H, dt, J=11.6, 2.4 Hz), 2.46 (3H, d, J=0.4 Hz), 3.03-3.09 (2H,m), 3.67 (2H, s), 3.84 (2H, d, J=6.0 Hz), 3.93 (3H, s), 6.82-6.89 (1H,m), 6.92 (1H, dt, J=8.8, 1.6 Hz), 6.98-7.08 (2H, m), 7.82 (1H, d, J=0.4Hz).

Example 2852-(2-Fluorophenyl)-1-[1-(3-methoxy-6-methyl-2-pyrazinylmethyl)piperidin-4-yl]ethanone

The title compound (130 mg, 48% yield) was obtained in the same manneras Example 1 from 118 mg of 3-methoxy-6-methylpyrazine-2-carboxaldehydeand 229 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.74-1.89 (4H, m), 2.16 (2H, dt, J=11.6,3.2 Hz), 2.39-2.48 (1H, m), 2.46 (3H, s), 3.01-3.08 (2H, m), 3.65 (2H,s), 3.76 (2H, s), 3.93 (3H, s), 7.00-7.10 (2H, m), 7.14 (1H, dt, J=7.6,1.6 Hz), 7.20-7.26 (1H, m), 7.82 (1H, s).

Example 2862-tert-Butoxy-3-[4-(2-chlorophenoxymethyl)-4-methylpiperidino]methyl-pyrazine

The title compound (237 mg, 88% yield) was obtained in the same manneras Example 269 from 120 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and192 mg of 4-(2-chlorophenoxymethyl)-4-methylpiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.13 (3H, s), 1.54-1.61 (2H, m), 1.60(9H, s), 1.70-1.78 (2H, m), 2.46-2.54 (2H, m), 2.63-2.70 (2H, m), 3.66(2H, s), 3.72 (2H, s), 6.82-6.90 (2H, m), 7.18 (1H, ddd, J=8.4, 7.6, 1.6Hz), 7.33 (1H, dd, J=7.6 1.6 Hz), 7.91 (1H, d, J=2.8 Hz), 8.03 (1H, d,J=2.8 Hz).

Example 2872-tert-Butoxy-3-[4-methyl-4-(2-methylphenoxymethyl)piperidino]methyl-pyrazine

The title compound (244 mg, 95% yield) was obtained in the same manneras Example 269 from 120 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and175 mg of 4-methyl-4-(2-methylphenoxymethyl)piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.10 (3H, s), 1.50-1.58 (2H, m), 1.60(9H, s), 1.70-1.78 (2H, m), 2.23 (3H, s), 2.46-2.54 (2H, m), 2.62-2.70(2H, m), 3.65 (2H, s), 3.67 (2H, s), 6.78 (1H, d, J=8.0 Hz), 6.82 (1H,t, J=7.2 Hz), 7.09-7.15 (2H, m), 7.90 (1H, d, J=2.4 Hz), 8.03 (1H, d,J=2.4 Hz).

Example 2882-tert-butoxy-3-[4-(2-methoxyphenoxymethyl)-4-methylpiperidino]methyl-pyrazine

The title compound (202 mg, 76% yield) was obtained in the same manneras Example 269 from 120 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and188 mg of 4-(2-methoxyphenoxymethyl)-4-methylpiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.11 (3H, s), 1.49-1.57 (2H, m), 1.60(9H, s), 1.71-1.79 (2H, m), 2.45-2.53 (2H, m), 2.63-2.70 (2H, m), 3.65(2H, s), 3.71 (2H, s), 3.83 (3H, s), 6.82-6.92 (4H, m), 7.90 (1H, d,J=2.8 Hz), 8.03 (1H, d, J=2.8 Hz).

Example 2891-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(methylsulfonyl)phenyl]ethanone

The title compound (196 mg, 83% yield) was obtained in the same manneras Example 1 from 115 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and169 mg of 2-[2-(methylsulfonyl)phenyl]-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.76-1.88 (2H, m),1.91-1.98 (2H, m), 2.07-2.26 (2H, m), 2.49-2.58 (1H, m), 3.00 (3H, s),3.03-3.10 (2H, m), 3.66 (2H, s), 4.36 (2H, s), 7.18 (1H, dd, J=7.6, 1.2Hz), 7.47 (1H, td, J=7.6, 1.2 Hz), 7.56 (1H, td, J=7.6, 1.4 Hz), 7.93(1H, d, J=2.8 Hz), 8.01 (1H, dd, J=7.6, 1.4 Hz), 8.04 (1H, d, J=2.8 Hz).

Example 2901-[1-(4-tert-Butoxy-5-pyrimidinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (205 mg, 17% yield) was obtained in the same manneras Example 89 from 0.72 g of ethyl 4-tert-butoxypyrimidine-5-carboxylateand 258 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.71-1.79 (2H, m),1.83-1.90 (2H, m), 2.08-2.14 (2H, m), 2.44 (1H, dt, J=11.6, 4.0 Hz),2.87-2.94 (2H, m), 3.42 (2H, s), 3.77 (2H, s), 7.00-7.11 (2H, m), 7.15(1H, dt, J=7.6, 2.0 Hz), 7.20-7.27 (1H, m), 8.36 (1H, s), 8.59 (1H, s)

Example 2911-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-biphenyl)ethanone

The title compound (210 mg, 75% yield) was obtained in the same manneras Example 1 from 137 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 2-(2-biphenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.53-1.64 (4H, m), 1.58 (9H, s),1.99-2.08 (2H, m), 2.09-2.18 (1H, m), 2.87-2.94 (2H, m), 3.57 (2H, s),3.71 (2H, s), 7.14-7.38 (9H, m), 7.90 (1H, d, J=2.8 Hz), 8.01 (1H, d,J=2.8 Hz).

Example 2922-(2-Fluorophenyl)-1-[1-(3-methoxy-2-pyrazinylmethyl)piperidin-4-yl]ethanone

The title compound (105 mg, 42% yield) was obtained in the same manneras Example 1 from 100 mg of 3-methoxypyrazine-2-carboxaldehyde and 224mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.76-1.90 (4H, m), 2.17 (2H, dt, J=11.2,3.2 Hz), 2.41-2.49 (1H, m), 3.01-3.07 (2H, m), 3.68 (2H, s), 3.76 (2H,s), 3.96 (3H, s), 6.99-7.10 (2H, m), 7.14 (1H, dt, J=7.6, 1.6 Hz),7.19-7.27 (1H, m), 7.98 (1H, d, J=2.8 Hz), 8.10 (1H, d, J=2.8 Hz).

Example 2931-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(4-fluorophenyl)ethanone

The title compound (254 mg, 85% yield) was obtained in the same manneras Example 1 from 168 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 2-(4-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.70-1.84 (4H, m),2.11-2.18 (2H, m), 2.35-2.44 (1H, m), 2.97-3.03 (2H, m), 3.62 (2H, s),3.70 (2H, s), 6.95-7.02 (2H, m), 7.09-7.14 (2H, m), 7.91 (1H, d, J=2.8Hz), 8.01 (1H, d, J=2.8 Hz).

Example 2945-Fluoro-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine

The title compound (93 mg, 35% yield) was obtained in the same manner asExample 1 from 120 mg of 6-fluoro-3-methoxypyrazine-2-carboxaldehyde and209 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.53 (2H, m), 1.81-1.92 (3H, m),2.14-2.22 (2H, m), 3.05-3.09 (2H, m), 3.65 (2H, s), 3.85 (2H, d, J=6.0Hz), 3.97 (3H, s), 6.83-6.89 (1H, m), 6.93 (1H, dt, J=8.8, 1.6 Hz),6.98-7.08 (2H, m), 7.81 (1H, d, J=8.4 Hz).

Example 2951-[1-(6-Fluoro-3-methoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (95 mg, 34% yield) was obtained in the same manner asExample 1 from 120 mg of 6-fluoro-3-methoxypyrazine-2-carboxaldehyde and219 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.74-1.90 (4H, m), 2.20 (2H, dt, J=11.2,2.8 Hz), 2.40-2.49 (1H, m), 3.01-3.07 (2H, m), 3.63 (2H, s), 3.76 (2H,s), 3.96 (3H, s), 7.00-7.10 (2H, m), 7.14 (1H, dt, J=7.6, 1.6 Hz),7.20-7.26 (1H, m), 7.81 (1H, d, J=8.4 Hz).

Example 2962-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrile

The title compound (188 mg, 64% yield) was obtained in the same manneras Example 1 from 161 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 3-(2-fluorophenyl)-2-(piperidin-4-yl)propionitrilehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.50-1.70 (3H, m), 1.60 (9H, s),1.74-1.81 (1H, m), 1.87-1.94 (1H, m), 2.08-2.17 (2H, m), 2.70-2.84 (2H,m), 3.01-3.11 (3H, m), 3.64 (2H, s), 7.04 (1H, ddd, J=9.6, 7.6, 1.2 Hz),7.10 (1H, td, J=7.6, 1.2 Hz), 7.22-7.30 (2H, m), 7.92 (1H, d, J=2.8 Hz),8.03 (1H, d, J=2.8 Hz).

Example 2972-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrile

The title compound (206 mg, 77% yield) was obtained in the same manneras Example 1 from 115 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of2-(2-fluorobenzyl)-3-(2-fluorophenyl)-2-(piperidin-4-yl)propionitrilehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.56-1.63 (1H, m), 1.57 (9H, s),1.67-1.80 (2H, m), 1.94-2.09 (4H, m), 2.82 (2H, d, J=14.0 Hz), 3.04 (2H,d, J=14.0 Hz), 3.10-3.18 (2H, m), 3.62 (2H, s), 7.05 (2H, ddd, J=9.6,7.6, 1.2 Hz), 7.11 (2H, td, J=7.6, 1.2 Hz), 7.23-7.30 (2H, m), 7.35 (2H,td, J=7.6, 1.6 Hz), 7.84 (2H, br s).

Example 2982-(2-Bromophenyl)-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]ethanone

The title compound (461 mg, 82% yield) was obtained in the same manneras Example 1 from 271 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and400 mg of 2-(2-bromophenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.77-1.93 (4H, m),2.14-2.22 (2H, m), 2.42-2.51 (1H, m), 2.99-3.06 (2H, m), 3.63 (2H, s),3.90 (2H, s), 7.11 (1H, td, J=7.6, 2.0 Hz), 7.16 (1H, dd, J=7.6, 2.0Hz), 7.22-7.28 (1H, m), 7.54 (1H, dd, J=7.6, 1.2 Hz), 7.91 (1H, d, J=2.8Hz), 8.02 (1H, d, J=2.8 Hz).

Example 2991-(3-tert-Butoxy-2-pyrazinylmethyl)-3-[2-(2-fluorophenyl)ethyl]piperidin-4-one

The title compound (207 mg, 65% yield) was obtained in the same manneras Example 269 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and203 mg of 3-[2-(2-fluorophenyl)ethyl]-4-oxopiperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.53 (1H, m), 1.60 (9H, s),2.07-2.17 (1H, m), 2.31-2.40 (2H, m), 2.56-2.70 (5H, m), 3.15-3.21 (1H,m), 3.23-3.39 (1H, m), 3.76 (2H, s), 6.93-6.98 (1H, m), 7.01 (1H, dt,J=7.2, 1.6 Hz), 7.11-7.17 (2H, m), 7.95 (1H, d, J=2.8 Hz), 8.05 (1H, d,J=2.8 Hz).

Example 3002-(2-Fluorophenyl)-1-[1-(3-methoxy-4-pyridazinylmethyl)piperidin-4-yl]ethanone

After dissolving 527 mg of methyl 3-methoxypyridazine-4-carboxylate in10 ml of toluene, 2 ml of diisobutylaluminium hydride (1.5 M, toluenesolution) was added dropwise while stirring at below −70° C., and thestirring was continued for 40 minutes. Next, 1N hydrochloric acid wasadded and the temperature was raised to room temperature. Dilutedammonia water was added to the reaction solution and extraction wasperformed with dichloromethane. The extract was washed with saturatedaqueous sodium bicarbonate solution and saturated brine in that orderand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was dissolved in 3 ml ofdichloromethane, and then 150 mg of2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride and 123 mgof sodium triacetoxyborohydride were added and the mixture was stirredfor 2 days at room temperature. A 1N sodium hydroxide solution was addedto the reaction mixture and extraction was performed with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (74 mg, 37% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.73-1.84 (2H, m), 1.85-1.93 (2H, m),2.13-2.21 (2H, m), 2.46-2.55 (1H, m), 2.85-2.92 (2H, m), 3.47 (2H, d,J=1.2 Hz), 3.79 (2H, d, J=1.2 Hz), 4.13 (3H, s), 7.05 (1H, ddd, J=9.6,7.6, 1.2 Hz), 7.09 (1H, td, J=7.6, 1.2 Hz), 7.16 (1H, td, J=7.6, 1.6Hz), 7.22-7.28 (1H, m), 7.48 (1H, dt, J=4.8, 1.2 Hz), 8.77 (1H, d, J=4.8Hz).

Example 3011-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-4-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone

After suspending 126 mg of2-(2-fluorophenyl)-1-(4-methylpiperidin-4-yl)ethanone hydrochloride in 3ml of dichloromethane, 100 mg of 3-tert-butoxypyrazine-2-carboxaldehydeand 146 mg of sodium triacetoxyborohydride were added and the mixturewas stirred overnight at room temperature. The reaction mixture wasdiluted with ethyl acetate, saturated aqueous sodium bicarbonatesolution was added and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate) to obtain the title compound (135 mg,69% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.22 (3H, s), 1.58-1.70 (2H, m), 1.59(9H, s), 2.14-2.22 (2H, m), 2.32-2.41 (2H, m), 2.67-2.74 (2H, m), 3.60(2H, s), 3.80 (2H, d, J=0.8 Hz), 6.99-7.05 (1H, m), 7.08 (1H, dt, J=7.2,1.2 Hz), 7.14 (1H, dt, J=7.2, 1.6 Hz), 7.20-7.26 (1H, m), 7.90 (1H, d,J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 302trans-1-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-3-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (112 mg, 47% yield) was obtained in the same manneras Example 1 from 100 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and181 mg of trans-2-(2-fluorophenyl)-1-(3-methylpiperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.78 (3H, d, J=6.4 Hz), 1.59 (9H, s),1.66-1.82 (3H, m), 2.03-2.21 (3H, m), 2.93-2.99 (1H, m), 3.03-3.09 (1H,m), 3.61 (1H, d, J=14.0 Hz), 3.65 (1H, d, J=14.0 Hz), 3.73 (1H, d,J=18.0 Hz), 3.77 (1H, d, J=18.0 Hz), 7.00-7.11 (2H, m), 7.14 (1H, dt,J=7.6, 1.6 Hz), 7.20-7.26 (1H, m), 7.92 (1H, d, J=2.8 Hz), 8.03 (1H, d,J=2.8 Hz).

Example 3032-tert-Butoxy-6-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine

The title compound (202 mg, 65% yield) was obtained in the same manneras Example 1 from 150 mg of 6-tert-butoxypyrazine-2-carboxaldehyde and246 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.49 (2H, m), 1.59 (9H, s),1.80-1.92 (3H, m), 2.16 (2H, dt, J=11.6, 2.0 Hz), 2.96-3.02 (2H, m),3.60 (2H, s), 3.86 (2H, d, J=6.4 Hz), 6.83-6.90 (1H, m), 6.93 (1H, dt,J=8.0, 1.6 Hz), 7.00-7.08 (2H, m), 7.95 (1H, s), 8.13 (1H, s).

Example 3041-[1-(6-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (172 mg, 56% yield) was obtained in the same manneras Example 1 from 150 mg of 6-tert-butoxypyrazine-2-carboxaldehyde and258 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.71-1.82 (2H, m),1.84-1.91 (2H, m), 2.16 (2H, dt, J=11.6, 2.8 Hz), 2.40-2.49 (1H, m),2.94-3.00 (2H, m), 3.58 (2H, s), 3.77 (2H, d, J=1.2 Hz), 7.00-7.11 (2H,m), 7.15 (1H, dt, J=7.2, 2.0 Hz), 7.21-7.27 (1H, m), 7.95 (1H, s), 8.11(1H, s).

Example 3051-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(3-pyridyl)ethanone

After dissolving 399 mg of1-(1-benzylpiperidin-4-yl)-2-(3-pyridyl)ethanone in 5 ml of methanol,206 mg of 10% palladium-carbon and 504 mg of ammonium formate were addedand the mixture was heated to reflux for 2.5 hours. The reaction mixturewas filtered and the solvent of the filtrate was distilled off underreduced pressure. The residue was dissolved in 5 ml of dichloromethane,346 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 407 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. Water and a 1N sodium hydroxide solution were addedto the reaction mixture to render it alkaline, and then extraction wasperformed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (173 mg, 29% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.70-1.90 (4H, m),2.14-2.27 (2H, m), 2.38-2.48 (1H, m), 3.00-3.08 (2H, m), 3.66 (2H, s),3.74 (2H, s), 7.22-7.27 (1H, m), 7.51 (1H, ddd, J=7.8, 2.4, 1.8 Hz),7.92 (1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz), 8.40 (1H, d, J=2.4 Hz),8.49 (1H, dd, J=4.8, 1.8 Hz).

Example 3061-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-4-fluoropiperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (210 mg, 63% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and276 mg of 2-(2-fluorophenyl)-1-(4-fluoropiperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.80-1.89 (2H, m),2.04-2.24 (2H, m), 2.49 (2H, dt, J=12.0, 1.6 Hz), 2.87-2.94 (2H, m),3.68 (2H, s), 3.99 (2H, dd, J=2.4, 1.2 Hz), 7.00-7.17 (3H, m), 7.21-7.27(1H, m), 7.92 (1H, d, J=2.8 Hz), 8.03 (1H, d, J=2.8 Hz).

Example 3072-tert-Butoxy-3-[4-[2-(2-fluorophenyl)ethyl]-3,3-dimethoxypiperidino]methyl-pyrazine

The title compound (165 mg, 69% yield) was obtained in the same manneras Example 1 from 130 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and169 mg of 3,3-dimethoxy-4-[2-(2-fluorophenyl)ethyl]piperidinehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.54-1.62 (3H, m), 1.59 (9H, s),1.80-1.87 (1H, m), 1.98-2.12 (2H, m), 2.44-2.57 (2H, m), 2.69-2.83 (3H,m), 3.04 (3H, s), 3.15 (3H, s), 3.66 (2H, s), 6.98 (1H, ddd, J=9.6, 7.6,1.2 Hz), 7.03 (1H, td, J=7.6, 1.2 Hz), 7.11-7.20 (2H, m), 7.90 (1H, d,J=2.8 Hz), 7.98 (1H, d, J=2.8 Hz).

Example 3081-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-4-fluoropiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone

The title compound (211 mg, 56% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and326 mg of1-(4-fluoropiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.82-1.92 (2H, m),2.04-2.24 (2H, m), 2.45-2.54 (2H, m), 2.87-2.95 (2H, m), 3.68 (2H, s),4.18 (2H, d, J=1.2 Hz), 7.18 (1H, d, J=7.6 Hz), 7.37 (1H, t, J=7.6 Hz),7.50 (1H, t, J=7.6 Hz), 7.64 (1H, d, J=7.6 Hz), 7.92 (1H, d, J=2.8 Hz),8.03 (1H, d, J=2.8 Hz).

Example 3091-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-4-methylpiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone

The title compound (53 mg, 84% yield) was obtained in the same manner asExample 1 from 33 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 45 mgof 1-(4-methylpiperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.23 (3H, s), 1.60 (9H, s), 1.60-1.70(2H, m), 2.13-2.21 (2H, m), 2.36-2.46 (2H, m), 2.66-2.74 (2H, m), 3.63(2H, s), 4.02 (2H, s), 7.15 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz),7.49 (1H, t, J=7.6 Hz), 7.64 (1H, d, J=7.6 Hz), 7.91 (1H, d, J=2.8 Hz),8.03 (1H, d, J=2.8 Hz).

Example 3101-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propan-2-one

The title compound (145 mg, 50% yield) was obtained in the same manneras Example 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and272 mg of 4-[3-(2-fluorophenyl)-2-oxopropyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.23-1.35 (2H, m), 1.56-1.66 (2H, m),1.58 (9H, s), 1.78-1.91 (1H, m), 2.07-2.15 (2H, m), 2.39 (2H, d, J=6.4Hz), 2.89-2.96 (2H, m), 3.60 (2H, s), 3.69 (2H, s), 7.01-7.11 (2H, m),7.14 (1H, dt, J=7.2, 2.0 Hz), 7.20-7.27 (1H, m), 7.89 (1H, d, J=2.8 Hz),8.02 (1H, d, J=2.8 Hz).

Example 3111-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propanone

The title compound (124 mg, 42% yield) was obtained in the same manneras Example 1 from 110 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and272 mg of 1-(piperidin-4-yl)-3-(2-fluorophenyl)propanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58 (9H, s), 1.63-1.82 (4H, m),2.09-2.18 (2H, m), 2.21-2.30 (1H, m), 2.75 (2H, t, J=7.2 Hz), 2.89 (2H,t, J=7.2 Hz), 2.95-3.02 (2H, m), 3.61 (2H, s), 6.94-7.05 (2H, m),7.12-7.19 (2H, m), 7.91 (1H, d, J=2.4 Hz), 8.01 (1H, d, J=2.4 Hz).

Example 3121-[1-[1-(3-Methoxy-2-pyrazinyl)ethyl]piperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone

The title compound (117 mg, 6% yield) was obtained in the same manner asExample 280 from 702 mg of 2-acetyl-3-methoxypyrazine and 2.83 g of1-(piperidin-4-yl)-2-[2-(trifluoromethyl)phenyl]ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39 (3H, d, J=6.8 Hz), 1.66-1.89 (4H,m), 2.06-2.19 (2H, m), 2.32-2.41 (1H, m), 2.92-2.98 (1H, m), 3.10-3.19(1H, m), 3.92 (2H, d, J=1.2 Hz), 3.96 (3H, s), 4.17 (1H, q, J=6.8 Hz),7.19 (1H, d, J=7.6 Hz), 7.34 (1H, t, J=7.6 Hz), 7.48 (1H, t, J=7.6 Hz),7.62 (1H, d, J=7.6 Hz), 7.96 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.8 Hz).

Example 3131-[1-(3-Methoxy-5-methyl-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (352 mg, 75% yield) was obtained in the same manneras Example 1 from 200 mg of 3-methoxy-5-methylpyrazine-2-carboxaldehydeand 407 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.74-1.88 (4H, m), 2.15 (2H, dt, J=11.2,3.2 Hz), 2.39-2.48 (1H, m), 2.42 (3H, s), 2.98-3.04 (2H, m), 3.64 (2H,s), 3.76 (2H, s), 3.94 (3H, s), 6.99-7.10 (2H, m), 7.13 (1H, dt, J=7.2,1.6 Hz), 7.19-7.26 (1H, m), 7.96 (1H, s).

Example 3141-[1-(3-tert-Butoxy-5-fluoro-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (122 mg, 43% yield) was obtained in the same manneras Example 1 from 138 mg of3-tert-butoxy-5-fluoropyrazine-2-carboxaldehyde and 216 mg of2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.70-1.90 (4H, m),2.11-2.21 (2H, m), 2.49-2.58 (1H, m), 2.94-3.02 (2H, m), 3.62 (2H, s),3.76 (2H, s), 6.99-7.17 (3H, m), 7.19-7.27 (1H, m), 7.86 (1H, d, J=8.4Hz).

Example 3151-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethanone

The title compound (62 mg, 86% yield) was obtained in the same manner asExample 269 from 43 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 45mg of 2-[2-fluoro-6-(trifluoromethyl)phenyl]-1-(piperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.60 (9H, s), 1.78-1.95 (4H, m), 2.21(2H, dt, J=10.4, 3.2 Hz), 2.43-2.52 (1H, m), 3.01-3.08 (2H, m), 3.65(2H, s), 3.98 (2H, s), 7.24 (1H, t, J=8.8 Hz), 7.32-7.38 (1H, m), 7.44(1H, d, J=8.0 Hz), 7.92 (1H, d, J=2.8 Hz), 8.03 (1H, d, J=2.8 Hz).

Example 3161-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(3-methyl-2-thienyl)ethanone

The title compound (132 mg, 59% yield) was obtained in the same manneras Example 1 from 136 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and150 mg of 2-(3-methyl-2-thienyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.72-1.84 (4H, m), 2.12(3H, s), 2.11-2.21 (2H, m), 2.40-2.48 (1H, m), 2.97-3.04 (2H, m), 3.62(2H, s), 3.82 (2H, s), 6.81 (1H, d, J=5.2 Hz), 7.09 (1H, d, J=5.2 Hz),7.91 (1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 3171-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(3-pyridyl)phenyl]ethanone

The title compound (315 mg, 100% yield) was obtained in the same manneras Example 21 from 120 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and205 mg of 1-(piperidin-4-yl)-2-[2-(3-pyridyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.53-1.64 (4H, m), 1.59 (9H, s),2.03-2.11 (2H, m), 2.14-2.24 (1H, m), 2.91-2.98 (2H, m), 3.60 (2H, s),3.72 (2H, s), 7.18-7.41 (5H, m), 7.54-7.58 (1H, m), 7.93 (1H, d, J=2.8Hz), 8.03 (1H, d, J=2.8 Hz), 8.50 (1H, dd, J=2.4, 0.8 Hz), 8.59 (1H, dd,J=4.8, 1.6 Hz).

Example 318 Methyl2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzoate

The title compound (230 mg, 86% yield) was obtained in the same manneras Example 1 from 190 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and190 mg of 4-[2-(methoxycarbonyl)phenoxymethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.53 (2H, m), 1.60 (9H, s),1.83-1.95 (3H, m), 2.14-2.21 (2H, m), 3.01-3.08 (2H, m), 3.66 (2H, s),3.85 (2H, d, J=6.4 Hz), 3.87 (3H, s), 6.94-6.98 (2H, m), 7.40-7.46 (1H,m), 7.78 (1H, dd, J=8.0, 1.6 Hz), 7.92 (1H, d, J=2.8 Hz), 8.05 (1H, d,J=2.8 Hz).

Example 3191-[2-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]ethanone

The title compound (134 mg, 51% yield) was obtained in the same manneras Example 1 from 155 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and177 mg of 4-(2-acetylphenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.56 (2H, m), 1.61 (9H, s),1.80-1.94 (3H, m), 2.13-2.22 (2H, m), 2.63 (3H, s), 3.02-3.08 (2H, m),3.66 (2H, s), 3.90 (2H, d, J=6.4 Hz), 6.91-7.00 (2H, m), 7.41-7.46 (1H,m), 7.72 (1H, dd, J=8.0, 2.0 Hz), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d,J=2.8 Hz).

Example 3202-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzamide

After dissolving 106 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and105 mg of 4-(2-carbamoylphenoxymethyl)piperidine in 5 ml ofdichloromethane, 153 mg of sodium triacetoxyborohydride was added andthe mixture was stirred overnight at room temperature. Aqueous sodiumbicarbonate solution was added to the reaction mixture and extractionwas performed with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. The residue waspurified by NH silica gel column chromatography (solvent: n-hexane/ethylacetate) to obtain the title compound (171 mg, 95% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.59 (2H, m), 1.61 (9H, s),1.77-1.95 (3H, m), 2.14-2.22 (2H, m), 3.03-3.09 (2H, m), 3.66 (2H, s),3.98 (2H, d, J=6.4 Hz), 5.77 (1H, br s), 6.96 (1H, d, J=7.6 Hz),7.04-7.10 (1H, m), 7.42-7.48 (1H, m), 7.76 (1H, br s), 7.93 (1H, d,J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz), 8.20 (1H, dd, J=8.0, 1.6 Hz).

Example 3212-tert-Butoxy-3-[4-(2-nitrophenoxymethyl)piperidino]methyl-pyrazine

The title compound (183 mg, 95% yield) was obtained in the same manneras Example 1 from 114 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and132 mg of 4-(2-nitrophenoxymethyl)piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.39-1.52 (2H, m), 1.61 (9H, s),1.82-1.94 (3H, m), 2.12-2.21 (2H, m), 3.00-3.07 (2H, m), 3.66 (2H, s),3.90 (2H, d, J=6.4 Hz), 6.97-7.07 (2H, m), 7.47-7.52 (1H, m), 7.81 (1H,dd, J=8.0, 1.6 Hz), 7.92 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=2.4 Hz).

Example 322N-[2-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]acetamide

The title compound (130 mg, 60% yield) was obtained in the same manneras Example 1 from 115 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and150 mg of 4-[2-(acetylamino)phenoxymethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.57 (2H, m), 1.61 (9H, s),1.76-1.93 (3H, m), 2.14-2.22 (5H, m), 3.02-3.09 (2H, m), 3.67 (2H, s),3.88 (2H, d, J=6.4 Hz), 6.85 (1H, dd, J=8.0, 1.2 Hz), 6.92-7.04 (2H, m),7.73 (1H, br s), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz), 8.34(1H, dd, J=8.0, 1.6 Hz).

Example 323N-[2-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]methanesulfonamide

The title compound (140 mg, 33% yield) was obtained in the same manneras Example 320 from 190 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and271 mg of 4-[2-(methanesulfonylamino)phenoxymethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.54 (2H, m), 1.61 (9H, s),1.75-1.91 (3H, m), 2.13-2.22 (2H, m), 2.94 (3H, s), 3.01-3.08 (2H, m),3.66 (2H, s), 3.86 (2H, d, J=6.4 Hz), 6.77 (1H, br s), 6.89 (1H, dd,J=8.4, 1.2 Hz), 6.93-6.99 (1H, m), 7.09-7.14 (1H, m), 7.54 (1H, dd,J=8.0, 1.6 Hz), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 3242-tert-Butoxy-3-[4-[2-(dimethylamino)phenoxymethyl]piperidino]methyl-pyrazine

The title compound (205 mg, 62% yield) was obtained in the same manneras Example 320 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and233 mg of 4-[2-(dimethylamino)phenoxymethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.43-1.55 (2H, m), 1.60 (9H, s),1.84-2.01 (3H, m), 2.13-2.21 (2H, m), 2.79 (6H, s), 3.01-3.08 (2H, m),3.65 (2H, s), 3.84 (2H, d, J=6.8 Hz), 6.82-6.96 (4H, m), 7.92 (1H, d,J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 3253-[2-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]-1-methylthiourea

The title compound (76 mg, 27% yield) was obtained in the same manner asExample 1 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 200mg of 4-[2-(3-methylthioureido)phenoxymethyl]piperidine hydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.40-1.52 (2H, m), 1.61 (9H, s),1.77-1.98 (3H, m), 2.12-2.20 (2H, m), 3.00-3.07 (2H, m), 3.13 (3H, d,J=4.4 Hz), 3.65 (2H, s), 3.81 (2H, d, J=6.4 Hz), 6.22-6.31 (1H, m),6.92-7.00 (2H, m), 7.20 (1H, dt, J=8.0, 1.6 Hz), 7.28-7.42 (1H, m), 7.52(1H, br s), 7.93 (1H, d, J=2.8 Hz), 8.05 (1H, d, J=2.8 Hz).

Example 3263-[2-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]-1-methylurea

The title compound (337 mg, 95% yield) was obtained in the same manneras Example 320 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and260 mg of 4-[2-(3-methylureido)phenoxymethyl]piperidine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.61 (9H, s), 1.64-1.88 (5H, m),2.12-2.20 (2H, m), 2.84 (3H, d, J=4.8 Hz), 3.02-3.09 (2H, m), 3.65 (2H,s), 3.87 (2H, d, J=4.8 Hz), 5.34 (1H, br s), 6.78-6.83 (1H, m), 6.85(1H, br s), 6.89-6.96 (2H, m), 7.95 (1H, d, J=2.8 Hz), 8.00-8.06 (2H,m).

Example 3271-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(4-fluoro-3-thienyl)ethanone

The title compound (262 mg, 88% yield) was obtained in the same manneras Example 1 from 178 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and200 mg of 2-(4-fluoro-3-thienyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.71-1.88 (4H, m),2.13-2.21 (2H, m), 2.37-2.46 (1H, m), 2.98-3.05 (2H, m), 3.63 (2H, s),3.66 (2H, d, J=0.8 Hz), 6.69 (1H, dd, J=3.6, 0.8 Hz), 7.02 (1H, tt,J=3.6, 0.8 Hz), 7.91 (1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 3282-tert-Butoxy-3-[4-(2-fluorophenoxymethyl)azepan-1-yl]methyl-pyrazine

The title compound (109 mg, 65% yield) was obtained in the same manneras Example 269 from 93 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and100 mg of 4-(2-fluorophenoxymethyl)azepane.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.50-2.20 (16H, m), 2.79-2.96 (4H, m),3.77 (2H, d, J=2.4 Hz), 3.82 (2H, d, J=6.8 Hz), 6.84-7.08 (4H, m), 7.92(1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 3291-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-cyanophenyl)ethanone

After dissolving 298 mg of2-(2-bromophenyl)-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]ethanonein 2 ml of N,N-dimethylformamide, 235 mg of zinc cyanide and 77 mg oftetrakis(triphenylphosphine) palladium(0) were added and the mixture wasstirred overnight at 100° C. A 1N sodium hydroxide solution was added tothe reaction mixture and extraction was performed with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (90 mg, 34% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.56 (9H, s), 1.77-1.88 (2H, m),1.88-1.96 (2H, m), 2.16-2.25 (2H, m), 2.45-2.55 (1H, m), 3.01-3.08 (2H,m), 3.64 (2H, m), 4.00 (2H, s), 7.28 (1H, d, J=7.6 Hz), 7.35 (1H, td,J=7.6, 1.2 Hz), 7.53 (1H, td, J=7.6, 1.2 Hz), 7.63 (1H, dd, J=7.6, 1.2Hz), 7.92 (1H, d, J=2.8 Hz), 8.02 (1H, d, J=2.8 Hz).

Example 3301-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2,3-dihydrobenzofuran-7-yl)ethanone

The title compound (107 mg, 86% yield) was obtained in the same manneras Example 1 from 66 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 86mg of 2-(2,3-dihydrobenzofuran-7-yl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.70-1.88 (4H, m),2.12-2.19 (2H, m), 2.38-2.47 (1H, m), 2.97-3.03 (2H, m), 3.21 (2H, t,J=8.8 Hz), 3.62 (2H, s), 3.68 (2H, s), 4.53 (2H, t, J=8.8 Hz), 6.79 (1H,t, J=7.4 Hz), 6.90 (1H, d, J=7.4 Hz), 7.09 (1H, dd, J=7.4, 1.2 Hz), 7.92(1H, d, J=2.8 Hz), 8.03 (1H, d, J=2.8 Hz).

Example 3312-tert-Butoxy-3-[4-(2-fluorophenoxymethyl)-4-methylpiperidino]methyl-pyrazine

4-(2-Fluorophenoxymethyl)-4-methylpiperidine hydrochloride (203 mg) wasobtained in the same manner as Production Example 113 from 203 mg of1-(tert-butoxycarbonyl)-4-(2-fluorophenoxymethyl)-4-methylpiperidine.The title compound (95 mg, 67% yield) was then obtained in the samemanner as Example 1 from 86 mg of 3-tert-butoxypyrazine-2-carboxaldehydeand 95 mg of the 4-(2-fluorophenoxymethyl)-4-methylpiperidinehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.11 (3H, s), 1.49-1.58 (2H, m), 1.60(9H, s), 1.74 (2H, ddd, J=13.6, 9.6, 4.0 Hz), 2.47-2.53 (2H, m),2.65-2.71 (2H, m), 3.67 (2H, s), 3.73 (2H, s), 6.83-6.91 (1H, m), 6.95(1H, td, J=8.4, 2.0 Hz), 6.99-7.08 (2H, m), 7.92 (1H, d, J=2.6 Hz), 8.05(1H, d, J=2.6 Hz).

Example 3321-[1-(3-tert-Butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluoro-3-thienyl)ethanone

The title compound (114 mg, 63% yield) was obtained in the same manneras Example 1 from 107 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and120 mg of 1-(2-fluoro-3-thienyl)-1-(piperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.59 (9H, s), 1.70-1.87 (4H, m),2.13-2.21 (2H, m), 2.36-2.45 (1H, m), 2.98-3.05 (2H, m), 3.63 (2H, s),3.64 (2H, d, J=1.2 Hz), 6.59-6.63 (2H, m), 7.93 (1H, d, J=2.8 Hz), 8.03(1H, d, J=2.8 Hz).

Example 333(E)-3-[4-[2-[2-(Cyclohexylmethyloxy)phenyl]vinyl]piperidino]methyl-2-methoxypyrazine

After dissolving 131 mg of 3-methoxypyrazine-2-carboxaldehyde and 236 mgof (E)-4-[2-[2-(cyclohexylmethyloxy)phenyl]vinyl]piperidine in 3 ml of1,2-dichloroethane, 0.07 ml of acetic acid and 276 mg of sodiumtriacetoxyborohydride were added and the mixture was stirred overnightat room temperature. Aqueous sodium carbonate solution was added to thereaction mixture and extraction was performed with ethyl acetate. Theextract was washed with water and saturated brine and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate) to obtain the titlecompound (255 mg, 77% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.01-1.38 (5H, m), 1.58-1.92 (10H, m),2.08-2.24 (3H, m), 3.02-3.08 (2H, m), 3.71 (2H, s), 3.76 (2H, d, J=6.0Hz), 3.98 (3H, s), 6.18 (1H, dd, J=16.0, 7.2 Hz), 6.70 (1H, d, J=16.0Hz), 6.82 (1H, dd, J=8.0, 0.8 Hz), 6.87 (1H, dt, J=7.6, 0.8 Hz), 7.14(1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.40 (1H, dd, J=7.6, 1.6 Hz), 7.99 (1H,d, J=2.4 Hz), 8.13 (1H, d, J=2.4 Hz).

Example 334trans-1-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-2-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (228 mg, 64% yield) was obtained in the same manneras Example 269 from 150 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and216 mg of trans-2-(2-fluorophenyl)-1-(2-methylpiperidin-4-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.10 (3H, d, J=6.4 Hz), 1.59 (9H, s),1.64-1.71 (1H, m), 1.74-1.85 (2H, m), 1.93-2.01 (1H, m), 2.53-2.60 (1H,m), 2.64-2.79 (2H, m), 3.02-3.10 (1H, m), 3.63 (1H, d, J=14.0 Hz), 3.67(1H, d, J=14.0 Hz), 3.76 (2H, s), 7.00-7.10 (2H, m), 7.15 (1H, dt,J=7.6, 2.0 Hz), 7.20-7.26 (1H, m), 7.89 (1H, d, J=2.8 Hz), 7.99 (1H, d,J=2.8 Hz).

Example 335cis-1-[1-(3-tert-Butoxy-2-pyrazinylmethyl)-2-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone

The title compound (46 mg, 19% yield) was obtained in the same manner asExample 1 from 100 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 182mg of cis-2-(2-fluorophenyl)-1-(2-methylpiperidin-4-yl)ethanonehydrochloride.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.27 (3H, d, J=6.4 Hz), 1.47-1.57 (1H,m), 1.60 (9H, s), 1.64-1.72 (1H, m), 1.76-1.86 (2H, m), 2.18-2.26 (1H,m), 2.37-2.45 (1H, m), 2.47-2.56 (1H, m), 3.04-3.10 (1H, m), 3.48 (1H,d, J=13.6 Hz), 3.75 (2H, d, J=0.8 Hz), 4.08 (1H, d, J=13.6 Hz),7.00-7.10 (2H, m), 7.13 (1H, dt, J=7.2, 2.0 Hz), 7.19-7.26 (1H, m), 7.90(1H, d, J=2.8 Hz), 8.01 (1H, d, J=2.8 Hz).

Example 3363-[4-[(2-Fluorophenylthio)methyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (46 mg, 77% yield) was obtained in the same manner asExample 118 from 70 mg of2-tert-butoxy-3-[4-[(2-fluorophenylthio)methyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.37-1.65 (3H, m), 1.94-2.01 (2H, m),2.22-2.30 (2H, m), 2.86 (2H, d, J=6.8 Hz), 2.97-3.04 (2H, m), 3.84 (2H,s), 7.03-7.12 (2H, m), 7.20-7.27 (1H, m), 7.37 (1H, td, J=8.0, 2.0 Hz),7.91 (1H, d, J=2.4 Hz), 7.95 (1H, br s).

Example 3373-[4-[(2-Fluorophenylsulfinyl)methyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (16 mg, 43% yield) was obtained in the same manner asExample 118 from 43 mg of2-tert-butoxy-3-[4-[(2-fluorophenylsulfinyl)methyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.48-1.66 (2H, m), 1.76-1.84 (1H, m),2.10-2.42 (4H, m), 2.80-2.89 (2H, m), 2.97-3.10 (2H, m), 3.86 (2H, s),7.13 (1H, ddd, J=9.6, 8.0, 1.2 Hz), 7.40 (1H, td, J=8.0, 1.2 Hz),7.47-7.54 (1H, m), 7.82-7.93 (3H, m).

Example 3383-[4-[(2-Fluorophenylsulfonyl)methyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (32 mg, 77% yield) was obtained in the same manner asExample 118 from 48 mg of2-tert-butoxy-3-[4-[(2-fluorophenylsulfonyl)methyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.42-1.61 (2H, m), 1.96-2.05 (2H, m),2.14-2.36 (3H, m), 2.95-3.02 (2H, m), 3.26 (2H, d, J=6.4 Hz), 3.83 (2H,s), 7.23-7.30 (1H, m), 7.36 (1H, td, J=8.0, 1.2 Hz), 7.64-7.70 (1H, m),7.86-7.98 (3H, m).

Example 3396-Chloro-5-[4-(2-fluorobenzyloxy)piperidino]methyl-1H-pyrazin-2-one

The title compound (29 mg, 24% yield) was obtained in the same manner asExample 118 from 137 mg of5-tert-butoxy-3-chloro-2-[4-(2-fluorobenzyloxy)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.28-1.42 (2H, m), 1.72-1.87 (3H, m),2.25-2.36 (2H, m), 2.95-3.04 (2H, m), 3.71 (2H, s), 3.88 (2H, d, J=6.0Hz), 6.87-6.94 (1H, m), 7.06-7.21 (3H, m), 7.87 (1H, s).

Example 3403-[3-[2-(2-Fluorophenyl)ethyl]morpholin-1-yl]methyl-1H-pyrazin-2-one

The title compound (223 mg, 80% yield) was obtained in the same manneras Example 137 from 329 mg of2-tert-butoxy-3-[3-[2-(2-fluorophenyl)ethyl]morpholin-1-yl]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.64-1.84 (2H, m), 2.12 (1H, dd, J=11.2,10.0 Hz), 2.41 (1H, dt, J=11.2, 3.2 Hz), 2.64-2.73 (1H, m), 2.78-2.88(3H, m), 3.53-3.62 (1H, m), 3.73 (1H, dt, J=11.6, 2.4 Hz), 3.76 (1H, d,J=15.2 Hz), 3.80 (1H, d, J=15.2 Hz), 3.91-3.97 (1H, m), 6.95-7.05 (2H,m), 7.12-7.18 (2H, m), 7.62 (1H, br s), 7.73 (1H, d, J=3.2 Hz).

Example 341(E)-3-[3-[2-(2-Fluorophenyl)vinyl]morpholin-1-yl]methyl-1H-pyrazin-2-one

The title compound (120 mg, 79% yield) was obtained in the same manneras Example 137 from 178 mg of(E)-2-tert-butoxy-3-[3-[2-(2-fluorophenyl)vinyl]morpholin-1-yl]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.26 (1H, dt, J=11.2, 10.8 Hz), 2.47(1H, dt, J=11.2, 3.2 Hz), 2.86-2.92 (1H, m), 3.00-3.05 (1H, m),3.78-3.90 (3H, m), 3.98-4.04 (1H, m), 4.28-4.34 (1H, m), 6.23 (1H, dd,J=16.4, 6.0 Hz), 6.80 (1H, dd, J=16.4, 1.2 Hz), 6.88-7.09 (2H, m),7.16-7.23 (1H, m), 7.40 (1H, dt, J=7.6, 1.6 Hz), 7.56 (1H, br s), 7.70(1H, d, J=3.6 Hz).

Example 3423-[3-(2-Fluorophenoxymethyl)morpholin-1-yl]methyl-1H-pyrazin-2-one

The title compound (175 mg, 79% yield) was obtained in the same manneras Example 137 from 258 mg of2-tert-butoxy-3-[3-(2-fluorophenoxymethyl)morpholin-1-yl]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 2.35 (1H, dt, J=11.2, 5.6 Hz), 2.45 (1H,dt, J=11.2, 3.6 Hz), 2.86-2.92 (1H, m), 3.08-3.14 (1H, m), 3.79 (1H, d,J=15.6 Hz), 3.79-3.87 (2H, m), 3.94-4.13 (4H, m), 6.87-7.08 (4H, m),7.45-7.51 (1H, m), 7.65 (1H, d, J=3.6 Hz).

Example 3433-[4-[2-[2-(Methylthio)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 200 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(methylthio)phenyl]ethanonewhile cooling on ice, the mixture was stirred for 30 minutes. A 2Nsodium hydroxide solution was added to the reaction solution forneutralization, and extraction was performed with dichloromethane. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. Diethyl ether was added to the residue and the mixture wasfiltered to obtain the title compound (146 mg, 84% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.82-1.94 (2H, m), 1.94-2.02 (2H, m),2.28-2.38 (2H, m), 2.43 (3H, s), 2.54-2.64 (1H, m), 2.98-3.06 (2H, m),3.83 (2H, s), 3.89 (2H, s), 7.08-7.16 (2H, m), 7.23-7.29 (2H, m), 7.88(2H, br s).

Example 3443-[4-[2-[2-(Trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 249 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanonewhile cooling on ice, the mixture was stirred for 30 minutes. A 2Nsodium hydroxide solution was added to the reaction solution forneutralization, and extraction was performed with dichloromethane. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. Diethyl ether was added to the residue and the mixture wasfiltered to obtain the title compound (155 mg, 71% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.81-2.02 (4H, m), 2.30-2.40 (2H, m),2.52-2.62 (1H, m), 3.01-3.09 (2H, m), 3.84 (2H, s), 3.97 (2H, s), 7.22(1H, d, J=7.6 Hz), 7.38 (1H, t, J=7.6 Hz), 7.51 (1H, t, J=7.6 Hz), 7.65(1H, d, J=7.6 Hz), 7.86 (2H, br s).

Example 3453-[4-[2-[2-(Trifluoromethoxy)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (153 mg, 66% yield) was obtained in the same manneras Example 344 from 266 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(trifluoromethoxy)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-2.01 (4H, m), 2.29-2.39 (2H, m),2.51-2.60 (1H, m), 2.99-3.08 (2H, m), 3.82 (2H, s), 3.84 (2H, s),7.18-7.34 (4H, m), 7.87 (2H, br s).

Example 3466-Methyl-3-[1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]-3,4-dihydropyrido[2,3-e][1,3]oxazin-2-one

The title compound (20 mg, 63% yield) was obtained in the same manner asExample 365 from 37 mg of3-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-6-methyl-3,4-dihydropyrido[2,3-e][1,3]oxazin-2-one.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.84-1.91 (2H, m), 1.96-2.08 (2H, m),2.39-2.48 (2H, m), 2.52 (3H, s), 3.12-3.20 (2H, m), 3.85 (2H, s),4.32-4.42 (1H, m), 4.46 (2H, s), 7.06 (1H, d, J=8.0 Hz), 7.21 (1H, d,J=8.0 Hz), 7.70 (1H, br s), 7.76-7.80 (1H, m).

Example 3473-[4-[2-(2-Ethoxyphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (166 mg, 73% yield) was obtained in the same manneras Example 344 from 264 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-ethoxyphenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36 (3H, t, J=7.0 Hz), 1.78-1.98 (4H,m), 2.25-2.35 (2H, m), 2.51-2.61 (1H, m), 2.96-3.05 (2H, m), 3.72 (2H,s), 3.82 (2H, s), 4.01 (2H, t, J=7.0 Hz), 6.83 (1H, d, J=7.6 Hz), 6.89(1H, t, J=7.6 Hz), 7.10 (1H, dd, J=7.6, 1.6 Hz), 7.19-7.26 (1H, m),7.85-7.93 (2H, m).

Example 3483-[4-[2-(2-n-Propoxyphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (165 mg, 69% yield) was obtained in the same manneras Example 344 from 276 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-n-propoxyphenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.01 (3H, t, J=7.4 Hz), 1.71-1.96 (6H,m), 2.24-2.35 (2H, m), 2.50-2.60 (1H, m), 2.95-3.04 (2H, m), 3.73 (2H,s), 3.82 (2H, s), 3.90 (2H, t, J=6.6 Hz), 6.84 (1H, d, J=7.6 Hz), 6.89(1H, t, J=7.6 Hz), 7.10 (1H, dd, J=7.6, 1.6 Hz), 7.19-7.26 (1H, m),7.86-7.94 (2H, m).

Example 3493-[4-[2-(2-Fluorophenyl)propionyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (227 mg, 88% yield) was obtained in the same manneras Example 344 from 300 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)propanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.38 (3H, d, J=6.8 Hz), 1.58-1.65 (1H,m), 1.70-1.85 (2H, m), 1.91-1.98 (1H, m), 2.14-2.32 (2H, m), 2.43-2.52(1H, m), 2.88-3.03 (2H, m), 3.79 (2H, s), 4.25 (1H, q, J=6.8 Hz), 7.06(1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.11 (1H, dd, J=7.6, 1.2 Hz), 7.15 (1H,td, J=7.6, 2.0 Hz), 7.21-7.27 (1H, m), 7.84-7.92 (2H, m).

Example 3503-[1-[4-[2-(2-Fluorophenyl)acetyl]piperidino]ethyl]-1H-pyrazin-2-one

After dissolving 118 mg of1-[1-[1-(3-methoxy-2-pyrazinyl)ethyl]piperidin-4-yl]-2-(2-fluorophenyl)ethanonein 2 ml of ethanol, 6 ml of 4N hydrogen chloride/ethyl acetate was addedand the mixture was heated to reflux for 9 hours. Saturated aqueoussodium bicarbonate solution was added to the reaction solution andextraction was performed with ethyl acetate. The organic layer waswashed with water and saturated brine in that order and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified by NH silica gel columnchromatography (solvent: ethyl acetate/methanol), diethyl ether wasadded and the precipitate was filtered out to obtain the title compound(61 mg, 38% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44 (3H, d, J=6.8 Hz), 1.77-1.93 (2H,m), 1.95-2.04 (2H, m), 2.29-2.39 (1H, m), 2.47-2.61 (2H, m), 2.91-3.01(2H, m), 3.78 (2H, s), 3.96 (1H, q, J=6.8 Hz), 7.01-7.18 (3H, m),7.22-7.29 (1H, m), 7.93 (1H, d, J=2.4 Hz), 7.96 (1H, br s)

Example 351cis-3-[3-(2-Fluorophenoxymethyl)-4-hydroxypiperidino]methyl-1H-pyrazin-2-one

After dissolving 198 mg ofcis-1-(3-tert-butoxy-2-pyrazinylmethyl)-3-(2-fluorophenoxymethyl)piperidin-4-olin 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate wasadded while stirring on ice. After 1 hour, aqueous sodium bicarbonatesolution was added to the reaction solution and extraction was performedwith dichloromethane. The extract was dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.Diethyl ether was added to the residue and the mixture was filtered toobtain the title compound (68 mg, 40% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.86-2.00 (2H, m), 2.33-2.42 (1H, m),2.72-2.84 (4H, m), 3.90 (2H, s), 4.06-4.18 (2H, m), 4.26-4.30 (1H, m),6.88-6.98 (2H, m), 7.01-7.09 (2H, m), 7.84 (2H, br s).

Example 352trans-3-[3-(2-Fluorophenoxymethyl)-4-hydroxypiperidino]methyl-1H-pyrazin-2-one

The title compound (63 mg, 50% yield) was obtained in the same manner asExample 351 from 149 mg oftrans-1-(3-tert-butoxy-2-pyrazinylmethyl)-3-(2-fluorophenoxymethyl)piperidin-4-ol.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.77-1.89 (1H, m), 2.03-2.11 (1H, m),2.21-2.40 (3H, m), 3.00-3.08 (1H, m), 3.12-3.18 (1H, m), 3.70-3.78 (1H,m), 3.83 (1H, d, J=16.0 Hz), 3.87 (1H, d, J=16.0 Hz), 4.09 (1H, dd,J=9.6, 4.8 Hz), 4.16 (1H, dd, J=9.6, 4.8 Hz), 6.86-7.09 (4H, m), 7.71(1H, br s), 7.78 (1H, d, J=2.8 Hz).

Example 3533-[4-[2-(1-Naphthyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (126 mg, 65% yield) was obtained in the same manneras Example 344 from 224 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(1-naphthyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.88 (4H, m), 2.18-2.28 (2H, m),2.52-2.62 (1H, m), 2.95-3.02 (2H, m), 3.79 (2H, s), 4.18 (2H, s), 7.34(1H, d, J=6.8 Hz), 7.41-7.53 (3H, m), 7.78-7.91 (5H, m).

Example 3543-[4-(2-Chlorophenoxymethyl)-4-methylpiperidino]methyl-1H-pyrazin-2-one

After dissolving 237 mg of2-tert-butoxy-3-[4-(2-chlorophenoxymethyl)-4-methylpiperidino]methyl-pyrazinein 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate wasadded while stirring on ice. After 1 hour, aqueous sodium carbonatesolution was added to the reaction solution and extraction was performedwith ethyl acetate. The organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was distilled off under reduced pressure. Diethyl ether wasadded to the residue and the precipitate was filtered out to obtain thetitle compound (104 mg, 51% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.18 (3H, s), 1.62-1.69 (2H, m),1.82-1.91 (2H, m), 2.58-2.68 (2H, m), 2.75-2.84 (2H, m), 3.76 (2H, s),3.89 (2H, s), 6.86-6.92 (2H, m), 7.19 (1H, dd, J=8.0, 1.6 Hz), 7.34 (1H,dd, J=8.4, 1.6 Hz), 7.90 (1H, d, J=2.8 Hz), 7.93 (1H, br s).

Example 3553-[4-Methyl-4-(2-methylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (135 mg, 64% yield) was obtained in the same manneras Example 354 from 244 mg of2-tert-butoxy-3-[4-methyl-4-(2-methylphenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.16 (3H, s), 1.57-1.65 (2H, m),1.83-1.92 (2H, m), 2.24 (3H, s), 2.57-2.67 (2H, m), 2.72-2.82 (2H, m),3.71 (2H, s), 3.89 (2H, s), 6.78 (1H, d, J=8.0 Hz), 6.85 (1H, t, J=7.6Hz), 7.10-7.17 (2H, m), 7.91 (1H, d, J=2.8 Hz), 7.94 (1H, br s).

Example 3563-[4-(2-Methoxyphenoxymethyl)-4-methylpiperidino]methyl-1H-pyrazin-2-one

The title compound (153 mg, 87% yield) was obtained in the same manneras Example 354 from 202 mg of2-tert-butoxy-3-[4-(2-methoxyphenoxymethyl)-4-methylpiperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.15 (3H, s), 1.58-1.66 (2H, m),1.81-1.90 (2H, m), 2.58-2.66 (2H, m), 2.76-2.84 (2H, m), 3.75 (2H, s),3.84 (3H, s), 3.88 (2H, s), 6.86-6.94 (4H, m), 7.87 (1H, d, J=2.8 Hz),7.91 (1H, d, J=2.8 Hz).

Example 3573-[4-[2-[2-(Methylsulfonyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (70 mg, 41% yield) was obtained in the same manner asExample 344 from 196 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(methylsulfonyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.84-1.96 (2H, m), 2.04-2.12 (2H, m),2.37-2.46 (2H, m), 2.62-2.72 (1H, m), 3.01 (3H, s), 3.05-3.13 (2H, m),3.88 (2H, s), 4.34 (2H, s), 7.19 (1H, dd, J=7.6, 1.2 Hz), 7.49 (1H, td,J=7.6, 1.2 Hz), 7.57 (1H, td, J=7.6, 1.6 Hz), 7.85 (2H, br s), 8.00 (1H,dd, J=7.6, 1.6 Hz).

Example 3585-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-3H-pyrimidin-4-one

The title compound (133 mg, 76% yield) was obtained in the same manneras Example 365 from 205 mg of1-[1-(4-tert-butoxy-5-pyrimidinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.83 (2H, m), 1.85-1.93 (2H, m),2.11-2.20 (2H, m), 2.48 (1H, dt, J=11.2, 4.0 Hz), 2.92-2.99 (2H, m),3.44 (2H, s), 3.78 (2H, s), 7.01-7.11 (2H, m), 7.15 (1H, dt, J=7.2, 2.0Hz), 7.21-7.27 (1H, m), 8.06 (1H, s), 8.13 (1H, s)

Example 3593-[4-[2-(2-Biphenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (155 mg, 85% yield) was obtained in the same manneras Example 344 from 210 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-biphenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.55-1.68 (4H, m), 2.14-2.28 (3H, m),2.84-2.93 (2H, m), 3.74 (2H, s), 3.78 (2H, s), 7.16-7.27 (4H, m),7.30-7.40 (5H, m), 7.85-7.92 (2H, m).

Example 3603-(2-Fluorophenyl)-2-[1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]propionitrile

After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 188 mg of2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrilewhile cooling on ice, the mixture was stirred 1 hour. A 2N sodiumhydroxide solution was added to the reaction solution forneutralization, and extraction was performed with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. Diethyl ether was added to the residue and the mixture wasfiltered to obtain the title compound (129 mg, 80% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.62-1.75 (3H, m), 1.85-1.94 (1H, m),2.00-2.08 (1H, m), 2.22-2.33 (2H, m), 2.76 (2H, m), 3.02-3.15 (3H, m),3.84 (2H, s), 7.06 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.12 (1H, td, J=7.6,1.2. Hz), 7.24-7.31 (2H, m), 7.86 (2H, br s).

Example 3612-(2-Fluorobenzyl)-3-(2-fluorophenyl)-2-[1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]propionitrile

The title compound (122 mg, 67% yield) was obtained in the same manneras Example 360 from 206 mg of2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorobenzyl)-3-(2-fluorophenyl)propionitrile.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.55-1.65 (1H, m), 1.72-1.84 (2H, m),2.06-2.13 (2H, m), 2.19-2.28 (2H, m), 2.84 (2H, d, J=14.0 Hz), 3.06 (2H,d, J=14.0 Hz), 3.14-3.22 (2H, m), 3.85 (2H, s), 7.07 (2H, ddd, J=9.2,7.6, 1.2 Hz), 7.14 (2H, td, J=7.6, 1.2 Hz), 7.24-7.32 (2H, m), 7.36 (2H,td, J=7.6, 2.0 Hz), 7.84 (2H, br s).

Example 3623-[4-[2-(2-Bromophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (39 mg, 84% yield) was obtained in the same manner asExample 344 from 53 mg of2-(2-bromophenyl)-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.83-1.95 (2H, m), 1.96-2.05 (2H, m),2.30-2.40 (2H, m), 2.55-2.65 (1H, m), 3.00-3.07 (2H, m), 3.84 (2H, s),3.92 (2H, s), 7.14 (1H, td, J=7.6, 1.6 Hz), 7.18 (1H, dd, J=7.6, 1.6Hz), 7.23-7.30 (1H, m), 7.56 (1H, dd, J=7.6, 1.2. Hz), 7.88 (2H, br s).

Example 3633-[4-[2-(2-Cyanophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (60 mg, 78% yield) was obtained in the same manner asExample 344 from 90 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-cyanophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.83-1.95 (2H, m), 2.00-2.08 (2H, m),2.32-2.42 (2H, m), 2.58-2.68 (1H, m), 3.02-3.10 (2H, m), 3.85 (2H, s),4.02 (2H, s), 7.28-7.32 (1H, m), 7.38 (1H, td, J=7.6, 1.2 Hz), 7.56 (1H,td, J=7.6, 1.6 Hz), 7.63-7.67 (1H, m), 7.86 (2H, br s).

Example 3644-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-2H-pyridazin-3-one

After dissolving 74 mg of2-(2-fluorophenyl)-1-[1-(3-methoxy-4-pyridazinylmethyl)piperidin-4-yl]ethanonein 2 ml of 5N hydrochloric acid, the mixture was heated to reflux for4.5 hours. A 5N sodium hydroxide solution was added to the reactionsolution for neutralization, and extraction was performed withdichloromethane. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,diethyl ether was added to the residue and the mixture was filtered toobtain the title compound (27 mg, 38% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.72-1.84 (2H, m), 1.85-1.93 (2H, m),2.16-2.24 (2H, m), 2.46-2.56 (1H, m), 2.85-2.94 (2H, m), 3.49 (2H, d,J=1.6 Hz), 3.79 (2H, s), 7.05 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.09 (1H,td, J=7.6, 1.2 Hz), 7.16 (1H, td, J=7.6, 1.6 Hz), 7.22-7.28 (1H, m),7.34-7.38 (1H, m), 7.78 (1H, d, J=4.4 Hz).

Example 3653-[4-[2-(2-Fluorophenyl)acetyl]-4-methylpiperidino]methyl-1H-pyrazin-2-one

After dissolving 135 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanonein 2 ml of ethyl acetate, 2 ml of 4N hydrogen chloride/ethyl acetate wasadded while stirring on ice. After 1 hour, saturated aqueous sodiumbicarbonate solution was added to the reaction solution and extractionwas performed with dichloromethane. The extract was dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. Diethyl ether was added to the residue and the mixture wasfiltered to obtain the title compound (94 mg, 86% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.29 (3H, s), 1.66-1.74 (2H, m),2.22-2.30 (2H, m), 2.39-2.51 (2H, m), 2.75-2.84 (2H, m), 3.80 (2H, s),3.81 (2H, s), 7.00-7.18 (3H, m), 7.22-7.28 (1H, m), 7.78-7.85 (2H, m).

Example 366trans-3-[4-[2-(2-Fluorophenyl)acetyl]-3-methylpiperidino]methyl-1H-pyrazin-2-one

The title compound (92 mg, 100% yield) was obtained in the same manneras Example 365 from 112 mg oftrans-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-3-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 0.82 (3H, d, J=6.4 Hz), 1.73-1.84 (1H,m), 1.87-1.98 (2H, m), 2.11-2.33 (3H, m), 2.93-2.99 (1H, m), 3.04-3.10(1H, m), 3.77 (2H, s), 3.82 (2H, s), 7.03-7.13 (2H, m), 7.16 (1H, dt,J=7.2, 1.6 Hz), 7.23-7.29 (1H, m), 7.86 (2H, br s)

Example 3676-[4-(2-Fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (153 mg, 89% yield) was obtained in the same manneras Example 365 from 202 mg of2-tert-butoxy-6-[4-(2-fluorophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.36-1.48 (2H, m), 1.84-1.96 (3H, m),2.21 (2H, dt, J=11.6, 2.4 Hz), 2.82-2.88 (2H, m), 3.40 (2H, s), 3.87(2H, d, J=6.4 Hz), 6.85-6.98 (2H, m), 7.02-7.10 (2H, m), 7.22 (1H, s),8.05 (1H, s).

Example 3686-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (135 mg, 91% yield) was obtained in the same manneras Example 365 from 172 mg of1-[1-(6-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.71-1.82 (2H, m), 1.86-1.94 (2H, m),2.22 (2H, dt, J=11.6, 2.8 Hz), 2.47-2.55 (1H, m), 2.81-2.87 (2H, m),3.39 (2H, s), 3.78 (2H, d, J=0.4 Hz), 7.02-7.07 (1H, m), 7.10 (1H, dt,J=7.2, 1.2 Hz), 7.16 (1H, dt, J=7.6, 2.0 Hz), 7.21-7.28 (2H, m), 8.05(1H, s).

Example 369 3-[4-[2-(3-Pyridyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (56 mg, 38% yield) was obtained in the same manner asExample 344 from 173 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(3-pyridyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.79-1.91 (2H, m), 1.92-2.00 (2H, m),2.28-2.38 (2H, m), 2.51-2.60 (1H, m), 3.01-3.09 (2H, m), 3.78 (2H, s),3.84 (2H, s), 7.25-7.30 (1H, m), 7.54 (1H, ddd, J=7.8, 2.4, 1.6 Hz),7.82 (1H, br s), 7.84 (1H, br s), 8.44 (1H, d, J=2.4 Hz), 8.53 (1H, dd,J=4.8, 1.6 Hz).

Example 3703-[4-Fluoro-4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (157 mg, 91% yield) was obtained in the same manneras Example 365 from 200 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-fluoropiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.88-1.97 (2H, m), 2.09-2.28 (2H, m),2.60 (2H, dt, J=12.0, 2.0 Hz), 2.93-3.00 (2H, m), 3.85 (2H, s), 4.00(2H, dd, J=2.4, 1.2 Hz), 7.02-7.17 (3H, m), 7.23-7.29 (1H, m), 7.66 (1H,br s), 7.75 (1H, d, J=3.2 Hz).

Example 3713-[4-[2-(2-Fluorophenyl)ethyl]-3-oxopiperidino]methyl-1H-pyrazin-2-one

The title compound (88 mg, 70% yield) was obtained in the same manner asExample 365 from 165 mg of2-tert-butoxy-3-[4-[2-(2-fluorophenyl)ethyl]-3,3-dimethoxypiperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.50-1.86 (2H, m), 2.15-2.34 (3H, m),2.64-2.74 (3H, m), 3.02 (1H, d, J=13.6 Hz), 3.08-3.17 (1H, m), 3.41 (1H,dd, J=13.4, 1.6 Hz), 3.79 (1H, d, J=15.0 Hz), 3.85 (1H, d, J=15.0 Hz),6.98 (1H, ddd, J=9.6, 7.6, 1.2 Hz), 7.04 (1H, td, J=7.6, 1.2 Hz),7.12-7.21 (2H, m), 7.37-7.42 (1H, m), 7.59 (1H, d, J=3.6 Hz).

Example 3723-[4-Fluoro-4-[2-[2-(trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (178 mg, 95% yield) was obtained in the same manneras Example 365 from 211 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-fluoropiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.90-1.99 (2H, m), 2.08-2.28 (2H, m),2.61 (2H, t, J=12.0 Hz), 2.94-3.01 (2H, m), 3.85 (2H, s), 4.19 (2H, s),7.20 (1H, d, J=7.6 Hz), 7.39 (1H, t, J=7.6 Hz), 7.51 (1H, t, J=7.6 Hz),7.61-7.68 (2H, m), 7.73-7.77 (1H, m).

Example 3733-[4-Methyl-4-[2-[2-(trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (37 mg, 78% yield) was obtained in the same manner asExample 365 from 53 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-4-methylpiperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.31 (3H, s), 1.66-1.76 (2H, m),2.19-2.29 (2H, m), 2.42-2.56 (2H, m), 2.74-2.84 (2H, m), 3.83 (2H, s),4.02 (2H, s), 7.17 (1H, d, J=7.6 Hz), 7.38 (1H, t, J=7.6 Hz), 7.51 (1H,t, J=7.6 Hz), 7.66 (1H, d, J=7.6 Hz), 7.86 (2H, br s).

Example 3743-[4-[3-(2-Fluorophenyl)-2-oxopropyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (118 mg, 95% yield) was obtained in the same manneras Example 365 from 145 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propan-2-one.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.26-1.38 (2H, m), 1.72-1.80 (2H, m),1.91-2.04 (1H, m), 2.26-2.74 (2H, m), 2.44 (2H, d, J=6.8 Hz), 2.92-2.98(2H, m), 3.70 (2H, s), 3.82 (2H, s), 7.03-7.12 (2H, m), 7.16 (1H, dt,J=7.2, 2.0 Hz), 7.23-7.29 (1H, m), 7.89 (1H, d, J=2.8 Hz), 7.94 (1H, brs).

Example 3753-[4-[3-(2-Fluorophenyl)propionyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (88 mg, 83% yield) was obtained in the same manner asExample 365 from 124 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propan-1-one.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.70-1.82 (2H, m), 1.85-1.93 (2H, m),2.24-2.42 (3H, m), 2.75-2.80 (2H, m), 2.92 (2H, t, J=7.6 Hz), 2.96-3.03(2H, m), 3.81 (2H, s), 6.96-7.06 (2H, m), 7.14-7.20 (2H, m), 7.86 (2H,br s).

Example 3763-[4-[2-[2-Fluoro-6-(trifluoromethyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (52 mg, 93% yield) was obtained in the same manner asExample 365 from 62 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.86-1.96 (2H, m), 1.98-2.08 (2H, m),2.33-2.42 (2H, m), 2.56-2.65 (1H, m), 3.02-3.09 (2H, m), 3.85 (2H, s),4.00 (2H, s), 7.23-7.29 (1H, m), 7.34-7.41 (1H, m), 7.46 (1H, d, J=8.0Hz), 7.86 (2H, br s).

Example 3773-[4-[2-(3-Methyl-2-thienyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (111 mg, 99% yield) was obtained in the same manneras Example 365 from 132 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(3-methyl-2-thienyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78-1.94 (4H, m), 2.13 (3H, s),2.28-2.35 (2H, m), 2.53-2.62 (1H, m), 2.98-3.06 (2H, m), 3.82 (2H, s),3.83 (2H, s), 6.82 (1H, d, J=5.2 Hz), 7.11 (1H, d, J=5.2 Hz), 7.85 (2H,br s).

Example 3783-[4-[2-[2-(3-Pyridyl)phenyl]acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (150 mg, 58% yield) was obtained in the same manneras Example 365 from 315 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(3-pyridyl)phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.58-1.74 (4H, m), 2.16-2.34 (3H, m),2.88-2.98 (2H, m), 3.74 (2H, s), 3.79 (2H, s), 7.18-7.28 (2H, m),7.32-7.42 (3H, m), 7.57 (1H, dt, J=8.0, 1.6 Hz), 7.85 (2H, br s), 8.50(1H, d, J=2.0 Hz), 8.61 (1H, dd, J=4.8, 1.6 Hz).

Example 379 Methyl2-[1-(3-oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzoate

The title compound (172 mg, 86% yield) was obtained in the same manneras Example 365 from 230 mg of methyl2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzoate.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.52-1.65 (2H, m), 1.93-2.05 (3H, m),2.31-2.40 (2H, m), 3.06-3.12 (2H, m), 3.88 (2H, s), 3.90 (3H, s), 3.92(2H, d, J=6.0 Hz), 6.92-7.01 (2H, m), 7.42-7.48 (1H, m), 7.80 (1H, dd,J=7.6, 1.6 Hz), 7.87-7.94 (2H, m).

Example 3803-[4-(2-Acetylphenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (99 mg, 85% yield) was obtained in the same manner asExample 365 from 134 mg of1-[2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.52-1.64 (2H, m), 1.93-2.06 (3H, m),2.31-2.40 (2H, m), 2.63 (3H, s), 3.06-3.15 (2H, m), 3.88 (2H, s), 3.94(2H, d, J=6.0 Hz), 6.94 (1H, d, J=7.6 Hz), 6.98-7.03 (1H, m), 7.42-7.48(1H, m), 7.72 (1H, dd, J=7.6, 1.6 Hz), 7.88 (2H, br s).

Example 3812-[1-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzamide

The title compound (80 mg, 54% yield) was obtained in the same manner asExample 365 from 171 mg of2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-benzamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.52-1.65 (2H, m), 1.88-2.06 (3H, m),2.28-2.37 (2H, m), 3.08-3.15 (2H, m), 3.85 (2H, s), 4.02 (2H, d, J=6.4Hz), 6.43 (1H, br s), 6.98 (1H, d, J=7.6 Hz), 7.06-7.12 (1H, m),7.44-7.50 (1H, m), 7.70 (1H, br s), 7.73 (1H, br s), 7.77-7.82 (1H, m),8.20 (1H, dd, J=8.0, 1.6 Hz).

Example 3823-[4-(2-Nitrophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (140 mg, 88% yield) was obtained in the same manneras Example 365 from 183 mg of2-tert-butoxy-3-[4-(2-nitrophenoxymethyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45-1.57 (2H, m), 1.96-2.06 (3H, m),2.29-2.38 (2H, m), 3.05-3.12 (2H, m), 3.87 (2H, s), 3.95 (2H, d, J=6.4Hz), 7.01-7.08 (2H, m), 7.50-7.55 (1H, m), 7.84 (1H, dd, J=8.0, 1.6 Hz),7.88 (2H, br s).

Example 383N-[2-[1-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]methanesulfonamide

The title compound (77 mg, 63% yield) was obtained in the same manner asExample 365 from 140 mg ofN-[2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]methanesulfonamide.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.45-1.58 (2H, m), 1.89-2.04 (3H, m),2.29-2.39 (2H, m), 2.96 (3H, s), 3.05-3.13 (2H, m), 3.88 (2H, s), 3.90(2H, d, J=6.4 Hz), 6.76 (1H, br s), 6.90 (1H, d, J=8.4 Hz), 6.96-7.01(1H, m), 7.10-7.16 (1H, m), 7.54 (1H, dd, J=8.0, 1.6 Hz), 7.80-7.93 (2H,m).

Example 3843-[4-[2-(Dimethylamino)phenoxymethyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (172 mg, 97% yield) was obtained in the same manneras Example 365 from 205 mg of2-tert-butoxy-3-[4-[2-(dimethylamino)phenoxymethyl]piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.51-1.65 (2H, m), 1.95-2.10 (3H, m),2.30-2.39 (2H, m), 2.79 (6H, s), 3.04-3.10 (2H, m), 3.87 (2H, s), 3.88(2H, d, J=6.0 Hz), 6.81-6.96 (4H, m), 7.88-7.96 (2H, m).

Example 3853-[2-[1-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]-1-methylthiourea

The title compound (47 mg, 71% yield) was obtained in the same manner asExample 365 from 76 mg of3-[2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]-1-methylthiourea.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.41-1.54 (2H, m), 1.92-2.02 (3H, m),2.30-2.38 (2H, m), 3.03-3.10 (2H, m), 3.14 (3H, d, J=4.0 Hz), 3.84 (2H,d, J=6.4 Hz), 3.87 (2H, s), 6.10-6.28 (1H, m), 6.92-7.01 (2H, m),7.19-7.38 (2H, m), 7.46 (1H, br s), 7.89 (2H, br s).

Example 3863-[2-[1-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]-1-methylurea

The title compound (181 mg, 62% yield) was obtained in the same manneras Example 365 from 337 mg of3-[2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]-1-methylurea.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.71-1.99 (5H, m), 2.30-2.40 (2H, m),2.86 (3H, d, J=4.8 Hz), 3.07-3.14 (2H, m), 3.86 (2H, s), 3.91 (2H, d,J=4.2 Hz), 5.57 (1H, br s), 6.78-6.84 (1H, m), 6.86-6.98 (3H, m),7.64-7.82 (2H, m), 8.00-8.06 (1H, m).

Example 3873-[4-[2-(4-Fluoro-3-thienyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (219 mg, 97% yield) was obtained in the same manneras Example 365 from 262 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(4-fluoro-3-thienyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78-1.90 (2H, m), 1.91-1.99 (2H, m),2.28-2.37 (2H, m), 2.50-2.58 (1H, m), 2.98-3.08 (2H, m), 3.68 (2H, d,J=0.4 Hz), 3.83 (2H, s), 6.71 (1H, d, J=3.2 Hz), 7.02-7.06 (1H, m),7.78-7.86 (2H, m).

Example 3883-[4-(2-Fluorophenoxymethyl)azepan-1-yl]methyl-1H-pyrazin-2-one

The title compound (63 mg, 68% yield) was obtained in the same manner asExample 118 from 109 mg of2-tert-butoxy-3-[4-(2-fluorophenoxymethyl)azepan-1-yl]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-2.24 (7H, m), 2.79-3.00 (4H, m),3.81-3.89 (2H, m), 3.97 (2H, s), 6.87-7.10 (4H, m), 7.89 (1H, d, J=2.8Hz), 7.95 (1H, d, J=2.8 Hz).

Example 3893-[4-[2-(4-Fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (131 mg, 76% yield) was obtained in the same manneras Example 344 from 201 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(4-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.76-1.95 (4H, m), 2.26-2.36 (2H, m),2.48-2.57 (1H, m), 2.97-3.05 (2H, m), 3.72 (2H, s), 3.82 (2H, s),6.98-7.04 (2H, m), 7.10-7.16 (2H, m), 7.86 (2H, br s).

Example 3903-[4-(2-Fluorophenoxymethyl)piperidino]methyl-5-methyl-1H-pyrazin-2-one

The title compound (70 mg, 56% yield) was obtained in the same manner asExample 364 from 130 mg of3-[4-(2-fluorophenoxymethyl)piperidino]methyl-2-methoxy-5-methylpyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.44-1.58 (2H, m), 1.91-2.03 (3H, m),2.28-2.37 (2H, m), 2.41 (3H, s), 3.01-3.08 (2H, m), 3.84 (2H, s), 3.88(2H, d, J=6.0 Hz), 6.85-6.97 (2H, m), 7.00-7.10 (2H, m), 7.86 (1H, s).

Example 3913-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-5-methyl-1H-pyrazin-2-one

The title compound (81 mg, 55% yield) was obtained in the same manner asExample 364 from 152 mg of2-(2-fluorophenyl)-1-[1-(3-methoxy-6-methyl-2-pyrazinylmethyl)piperidin-4-yl]ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78-1.90 (2H, m), 1.93-2.00 (2H, m),2.28-2.38 (2H, m), 2.40 (3H, s), 2.52-2.61 (1H, m), 2.97-3.04 (2H, m),3.78 (2H, s), 3.81 (2H, s), 6.92-7.12 (2H, m), 7.16 (1H, dt, J=7.6, 2.0Hz), 7.22-7.28 (1H, m), 7.84 (1H, s).

Example 3925-Fluoro-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (52 mg, 58% yield) was obtained in the same manner asExample 364 from 93 mg of5-fluoro-3-[4-(2-fluorophenoxymethyl)piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.59 (2H, m), 1.92-2.04 (3H, m),2.32-2.41 (2H, m), 3.01-3.08 (2H, m), 3.82 (2H, s), 3.89 (2H, d, J=6.0Hz), 6.86-6.97 (2H, m), 7.01-7.10 (2H, m), 7.88 (1H, d, J=8.0 Hz).

Example 3935-Fluoro-3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (76 mg, 83% yield) was obtained in the same manner asExample 364 from 95 mg of1-[1-(6-fluoro-3-methoxy-2-pyrazinyl)methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.79-1.92 (2H, m), 1.94-2.03 (2H, m),2.32-2.42 (2H, m), 2.54-2.64 (1H, m), 2.96-3.04 (2H, m), 3.79 (2H, s),3.80 (2H, s), 7.02-7.13 (2H, m), 7.16 (1H, dt, J=7.6, 1.6 Hz), 7.22-7.30(1H, m), 7.89 (1H, d, J=8.0 Hz).

Example 3943-[1-[4-[2-[2-(Trifluoromethyl)phenyl]acetyl]piperidino]ethyl]-1H-pyrazin-2-oneoxalate

After dissolving 117 mg of1-[1-[1-(3-methoxy-2-pyrazinyl)ethyl]piperidin-4-yl]-2-[2-(trifluoromethyl)phenyl]ethanonein 3 ml of 5N hydrochloric acid, the mixture was heated to reflux for 3hours. Aqueous sodium carbonate solution was added to the reactionsolution to render it alkaline, and extraction was performed withdichloromethane. The extract was dried over anhydrous magnesium sulfateand the solvent was distilled off under reduced pressure. The residuewas purified by NH silica gel column chromatography (solvent: ethylacetate/methanol).

The obtained product was dissolved in ethanol, and then 26 mg of oxalicacid anhydrous was added. Diethyl ether was added and the precipitatewas filtered out to obtain the title compound (100 mg, 71% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.43 (3H, d, J=6.8 Hz), 1.62-1.82 (2H,m), 1.95-2.06 (2H, m), 2.70-2.80 (1H, m), 2.82-2.94 (2H, m), 3.25-3.34(1H, m), 3.36-3.48 (1H, m), 4.10 (2H, s), 4.70 (1H, q, J=6.8 Hz), 7.35(1H, d, J=7.6 Hz), 7.41 (1H, d, J=4.0 Hz), 7.46 (1H, t, J=7.6 Hz), 7.52(1H, d, J=4.0 Hz) 7.61 (1H, t, J=7.6 Hz), 7.68 (1H, d, J=7.6 Hz).

Example 3953-[1-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-oneoxalate

3-[1-[4-(2-Fluorophenoxymethyl)piperidino]ethyl]-1H-pyrazin-2-one wasobtained in the same manner as Example 364 from 100 mg of2-[1-[4-(2-fluorophenoxymethyl)piperidino]ethyl]-3-methoxypyrazine, andwas then converted to an oxalate by an ordinary method to obtain thetitle compound (20 mg, 63% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.48 (3H, d, J=6.8 Hz), 1.50-1.76 (3H,m), 1.88-2.10 (3H, m), 2.95-3.09 (2H, m), 3.46-3.66 (1H, m), 3.94 (2H,d, J=5.2 Hz), 4.71-4.80 (1H, m), 6.89-6.96 (1H, m), 7.08-7.23 (3H, m),7.43 (1H, d, J=4.0 Hz), 7.56 (1H, d, J=4.0 Hz)

Example 3963-[3-[2-(2-Fluorophenyl)ethyl]-4-oxopiperidino]methyl-1H-pyrazin-2-oneoxalate

3-[3-[2-(2-fluorophenyl)ethyl]-4-oxopiperidino]methyl-1H-pyrazin-2-onewas obtained in the same manner as Example 365 from 207 mg of1-(3-tert-butoxy-2-pyrazinylmethyl)-3-[2-(2-fluorophenyl)ethyl]piperidin-4-one,and was then converted to an oxalate by an ordinary method to obtain thetitle compound (130 mg, 57% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.34-1.46 (1H, m), 1.90-2.02 (1H, m),2.24-2.32 (1H, m), 2.54-2.60 (5H, m), 2.80-2.89 (1H, m), 3.24-3.32 (1H,m), 3.34-3.42 (1H, m), 3.85 (1H, d, J=14.8 Hz), 3.90 (1H, d, J=14.8 Hz),7.07-7.15 (2H, m), 7.19-7.29 (2H, m), 7.31 (1H, d, J=4.0 Hz), 7.40 (1H,d, J=4.0 Hz).

Example 397N-[2-[1-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]acetamideoxalate

N-[2-[1-(3-Oxo-3,4-dihydro-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]acetamidewas obtained in the same manner as Example 365 from 130 mg ofN-[2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]methoxy-phenyl]acetamide,and was then converted to an oxalate by an ordinary method to obtain thetitle compound (112 mg, 78% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.54-1.66 (2H, m), 1.94-2.12 (6H, m),2.92-3.04 (2H, m), 3.40-3.52 (2H, m), 3.90 (2H, d, J=6.0 Hz), 4.23 (2H,s), 6.88-6.94 (1H, m), 7.00-7.10 (2H, m), 7.39 (1H, d, J=4.0 Hz), 7.52(1H, d, J=4.0 Hz), 7.81 (1H, d, J=7.6 Hz), 8.92 (1H, s).

Example 3983-[4-(2-Fluorobenzylsulfinyl)piperidino]methyl-1H-pyrazin-2-one

After dissolving 57 mg of3-[4-(2-fluorobenzylthio)piperidino]methyl-1H-pyrazin-2-one in 3 ml ofdichloromethane, 31 mg of 3-chloroperbenzoic acid was added at below−70° C., the mixture was stirred for 30 minutes, and then an additional5 mg of 3-chloroperbenzoic acid was added and the stirring was continuedfor 20 minutes. Aqueous sodium thiosulfate solution was added to thereaction solution and extraction was performed with dichloromethane. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(solvent: chloroform/methanol/ammonia water) to obtain the titlecompound (16 mg, 27% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.95-2.04 (2H, m), 2.32-2.45 (2H, m),2.63-2.73 (1H, m), 3.14-3.22 (2H, m), 3.45-3.52 (2H, m), 3.81 (2H, s),4.63 (2H, s), 7.04 (1H, ddd, J=9.8, 8.0, 1.2 Hz), 7.13 (1H, td, J=8.0,1.2 Hz), 7.22-7.29 (1H, m), 7.36 (1H, td, J=8.0, 2.0 Hz), 7.81 (1H, d,J=2.4 Hz), 8.16 (1H, d, J=2.4 Hz).

Example 3992-(2-Fluorophenyl)-1-[1-[(4-hydroxy-[1,2,5]thiadiazol-3-yl)methyl]piperidin-4-yl]ethanone

After dissolving 682 mg of 3-hydroxy-4-hydroxymethyl-[1,2,5]thiadiazolein 40 ml of tetrahydrofuran, 6.8 g of manganese dioxide was added andthe mixture was stirred overnight at room temperature. The reactionmixture was filtered and the filtrate was distilled off under reducedpressure. The residue was dissolved in tetrahydrofuran and the solutionwas filtered with celite. The filtrate was then distilled off underreduced pressure. The residue was suspended in 10 ml of tetrahydrofuran,486 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone and 513 mg ofsodium triacetoxyborohydride were added and the mixture was stirred for2 hours. The reaction mixture was concentrated under reduced pressure,water and diluted hydrochloric acid were added to the residue foradjustment to pH 4, and extraction was performed with chloroform. Theextract was dried over anhydrous magnesium sulfate, and then the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: chloroform/methanol). Diethylether was added and the mixture was filtered to obtain the titlecompound (179 mg, 10% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.80-1.92 (2H, m), 1.96-2.04 (2H, m),2.31-2.41 (2H, m), 2.55-2.64 (1H, m), 2.94-3.02 (2H, m), 3.79 (2H, d,J=1.2 Hz), 3.88 (2H, s), 7.02-7.13 (2H, m), 7.16 (1H, dt, J=7.2, 2.0Hz), 7.23-7.24 (1H, m).

Example 4006-Fluoro-3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

After dissolving 122 mg of1-[1-(3-tert-butoxy-5-fluoro-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanonein 3 ml of trifluoroacetic acid, the mixture was stirred for 1.5 hoursat room temperature. The reaction solution was cooled on ice, the pH wasadjusted to 7 with a 5% sodium hydroxide solution, and extraction wasperformed with dichloromethane. The extract was dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. Diethyl ether was added to the residue and the mixture wasfiltered to obtain the title compound (97 mg, 93% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.85-1.97 (2H, m), 1.99-2.07 (2H, m),2.42-2.54 (2H, m), 2.59-2.68 (1H, m), 2.94-3.12 (2H, m), 3.79 (2H, s),3.89 (2H, d, J=1.2 Hz), 7.02-7.13 (2H, m), 7.16 (1H, dt, J=7.6, 1.6 Hz),7.23-7.30 (1H, m), 7.72 (1H, d, J=8.4 Hz).

Example 4013-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-6-methyl-1H-pyrazin-2-one

After dissolving 352 mg of1-[1-(3-methoxy-5-methyl-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanonein 3 ml of dichloromethane, 0.5 ml of iodotrimethylsilane was added andthe mixture was stirred for 45 minutes at room temperature. Next, 2 mlof iodotrimethylsilane was added and the mixture was further stirred for2 hours at room temperature. Water was added to the reaction solution,the mixture was rendered alkaline with sodium carbonate, and extractionwas performed with dichloromethane. The extract was dried over anhydrousmagnesium sulfate and then the solvent was distilled off under reducedpressure. The residue was purified by NH silica gel columnchromatography (solvent: ethyl acetate/methanol). Diethyl ether wasadded and the mixture was filtered to obtain the title compound (92 mg,27% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.78-1.90 (2H, m), 1.91-1.98 (2H, m),2.25-2.34 (2H, m), 2.38 (3H, s), 2.50-2.59 (1H, m), 2.98-3.06 (2H, m),3.78 (4H, s), 7.01-7.12 (2H, m), 7.15 (1H, dt, J=7.6, 2.0 Hz), 7.22-7.28(1H, m), 7.69 (1H, br s).

Example 4023-[4-(2-Fluorophenoxymethyl)piperidino]methyl-1-methyl-1H-pyrazin-2-one

The title compound (28 mg, 42% yield) was obtained in the same manner asProduction Example 63 from 62 mg of3-[4-(2-fluorophenoxymethyl)piperidino]methyl-1H-pyrazin-2-one.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.46-1.59 (2H, m), 1.81-1.95 (3H, m),2.12-2.21 (2H, m), 3.08-3.15 (2H, m), 3.52 (3H, s), 3.71 (2H, s), 3.85(2H, d, J=6.4 Hz), 6.82-6.89 (1H, m), 6.90-6.96 (1H, m), 6.99-7.08 (3H,m), 7.30 (1H, d, J=4.4 Hz).

Example 4033-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-1-methyl-1H-pyrazin-2-one

After dissolving 300 mg of3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1-1H-pyrazin-2-one in 5ml of N,N-dimethylformamide, 113 mg of potassium tert-butoxide wasadded, the mixture was stirred for 30 minutes while cooling on ice,0.063 ml of methyl iodide was added and the stirring was continued for 1hour. Ice water was added to the reaction solution and extraction wasperformed with ethyl acetate. The organic layer was washed with waterand saturated brine in that order and dried over anhydrous magnesiumsulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (solvent:ethyl acetate/methanol). Diisopropyl ether was added and the mixture wasfiltered to obtain the title compound (61 mg, 20% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.79-1.92 (4H, m), 2.13-2.24 (2H, m),2.42-2.51 (1H, m), 3.08-3.14 (2H, m), 3.52 (3H, s), 3.70 (2H, s), 3.77(2H, s), 7.00-7.10 (3H, m), 7.14 (1H, dt, J=7.6, 1.6 Hz), 7.20-7.27 (1H,m), 7.29 (1H, d, J=4.4 Hz).

Example 4043-[4-(1,3-Dihydroisobenzofuran-1-carbonyl)piperidino]methyl-1H-pyrazin-2-one

After dissolving 517 mg of(1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanone in 5ml of 1,2-dichloroethane, 0.49 ml of 1-chloroethyl chloroformate wasadded and the mixture was heated to reflux for 1 hour. The reactionsolution was distilled off under reduced pressure, 5 ml of methanol wasadded to the residue and heating to reflux was continued for 1 hour. Thereaction solution was distilled off under reduced pressure, saturatedaqueous sodium bicarbonate solution was added and extraction wasperformed with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then the solvent was distilled off under reducedpressure to obtain 104 mg of(1,3-dihydroisobenzofuran-1-yl)-(piperidin-4-yl)methanone hydrochloride.

After then dissolving 93 mg of the(1,3-dihydroisobenzofuran-1-yl)-(piperidin-4-yl)methanone hydrochloridein 3 ml of tetrahydrofuran, 89 mg of3-tert-butoxypyrazine-2-carboxaldehyde, 130 mg of sodiumtriacetoxyborohydride and 0.03 ml of acetic acid were added whilestirring, and the stirring was continued overnight at room temperature.A 2N sodium hydroxide solution was added to the reaction mixture andextraction was performed with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and then the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate).

After dissolving the product in 1 ml of ethanol, 1 ml of 4N hydrogenchloride/ethyl acetate was added and the mixture was stirred for 30minutes at room temperature. The reaction solution was concentratedunder reduced pressure, a 2N sodium hydroxide solution was added andextraction was performed with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and then the solvent was distilled off underreduced pressure. Diethyl ether was added to the residue and theinsoluble portion was filtered out to obtain the title compound (8 mg,1% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.47-2.40 (6H, m), 2.89-3.07 (3H, m),3.81 (2H, s), 5.24-5.34 (2H, m), 5.54-5.57 (1H, m), 7.19-7.36 (4H, m),7.86 (2H, s).

Example 4055-[4-(2-Fluorophenoxymethyl)piperidino]methyl-2,4-dihydro-[1,2,4]triazol-3-one

After adding 150 mg of 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one,331 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride and 180 mgof anhydrous potassium carbonate to acetonitrile, the mixture wasstirred overnight at room temperature. Water and ethyl acetate wereadded to the reaction mixture and the insoluble portion was filtered outto obtain the title compound (70 mg, 21% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.26-1.38 (2H, m), 1.67-1.80 (3H, m),1.95-2.04 (2H, m), 2.77-2.84 (2H, m), 3.24 (2H, s), 3.88 (2H, d, J=5.6Hz), 6.87-6.94 (1H, m), 7.06-7.21 (3H, m), 11.19 (1H, s), 11.27 (1H, brs).

Example 4063-[4-(2-Fluorophenoxymethyl)-4-methylpiperidino]methyl-1H-pyrazin-2-one

The title compound (66 mg, 81% yield) was obtained in the same manner asExample 118 from 96 mg of2-tert-butoxy-3-[4-(2-fluorophenoxymethyl)-4-methylpiperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.17 (3H, s), 1.64 (2H, dt, J=14.4, 4.2Hz), 1.83 (2H, ddd, J=13.6, 9.6, 4.0 Hz), 2.59-2.68 (2H, m), 2.74-2.82(2H, m), 3.78 (2H, s), 3.89 (2H, s), 6.87-6.95 (1H, m), 6.96 (1H, td,J=8.4, 1.6 Hz), 7.01-7.10 (2H, m), 7.87-7.96 (2H, m).

Example 4073-[8-(2-Fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]non-3-yl]methyl-1H-pyrazin-2-one

After adding 191 mg of3-benzyloxycarbonyl-7-oxo-3-azabicyclo[4.3.0]nonane, 16 mg of palladiumacetate and 104 mg of BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) to 3 ml of toluene under anitrogen atmosphere, the mixture was stirred for 15 minutes, and then245 mg of o-bromofluorobenzene, 134 mg of sodium tert-butoxide and 6 mlof toluene were added and the mixture was stirred overnight at 100° C.Saturated aqueous ammonium chloride solution was added to the reactionsolution and extraction was performed with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate and the solvent was distilledoff under reduced pressure. The residue was purified by NH silica gelcolumn chromatography (solvent: n-hexane/ethyl acetate) to obtain 133 mgof3-benzyloxycarbonyl-8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonane.

After then dissolving 50 mg of the3-benzyloxycarbonyl-8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonanein 30 ml of methanol, 100 mg of 10% palladium-carbon was added and themixture was stirred for 4 days at room temperature under a hydrogenatmosphere (1 atm). The reaction mixture was filtered and the filtratewas distilled off under reduced pressure to obtain 62 mg of8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonane.

3-(3-tert-Butoxy-2-pyrazinylmethyl)-8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonanewas obtained in the same manner as Example 320 from 60 mg of3-tert-butoxypyrazine-2-carboxaldehyde and 60 mg of8-(2-fluorophenyl)-7-oxo-3-azabicyclo[4.3.0]nonane.

This was subjected to the same process as in Example 118 to obtain thetitle compound (43 mg, 49% yield).

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.90-2.11 (2H, m), 2.13-2.60 (3H, m),2.64-2.74 (1H, m), 2.80-2.94 (2H, m), 3.09 (1H, q, J=5.6 Hz), 3.57 (1H,t, J=10.2 Hz), 3.72-3.85 (3H, m), 7.00-7.15 (3H, m), 7.20-7.29 (1H, m),7.61-7.71 (1H, m), 7.71-7.81 (1H, m).

Example 4085-[4-[2-(2-Fluorophenyl)acetyl]piperidino]methyl-2,4-dihydro-[1,2,4]triazol-3-one

After adding 150 mg of 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one,335 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochlorideand 180 mg of anhydrous potassium carbonate to acetonitrile, the mixturewas stirred overnight at room temperature. Water was added to thereaction mixture and extraction was performed with ethyl acetate. Theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. Diethyl ether was added to the residue and themixture was filtered to obtain the title compound (23 mg, 7% yield).

1H-NMR (400 MHz, DMSO-d6); δ(ppm) 1.42-1.56 (2H, m), 1.79-1.87 (2H, m),1.98-2.07 (2H, m), 2.45-2.55 (1H, m), 2.75-2.82 (2H, m), 3.25 (2H, s),3.89 (2H, s), 7.09-7.16 (2H, m), 7.19-7.32 (2H, m), 11.20 (1H, s), 11.26(1H, br s).

Example 4093-[4-[2-(2-Fluoro-3-thienyl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (103 mg, 100% yield) was obtained in the same manneras Example 365 from 114 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluoro-3-thienyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.77-1.88 (2H, m), 1.90-1.98 (2H, m),2.28-2.37 (2H, m), 2.49-2.58 (1H, m), 2.99-3.07 (2H, m), 3.66 (2H, s),3.83 (2H, s), 6.60-6.66 (2H, m), 7.87 (2H, br s).

Example 4103-[4-[2-(2,3-Dihydrobenzofuran-7-yl)acetyl]piperidino]methyl-1H-pyrazin-2-one

The title compound (69 mg, 75% yield) was obtained in the same manner asExample 118 from 107 mg of1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-(2,3-dihydrobenzofuran-7-yl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.77-1.99 (4H, m), 2.27-2.37 (2H, m),2.52-2.61 (1H, m), 2.95-3.05 (2H, m), 3.23 (2H, t, J=8.8 Hz), 3.70 (2H,s), 3.83 (2H, s), 4.54 (2H, t, J=8.8 Hz), 6.81 (1H, t, J=7.4 Hz), 6.92(1H, d, J=7.4 Hz), 7.10 (1H, dd, J=7.4, 1.2 Hz), 7.90 (1H, br s), 7.92(1H, br s).

Example 411 3-[4-(2-Fluorobenzylthio)piperidino]methyl-1H-pyrazin-2-one

The title compound (180 mg, 94% yield) was obtained in the same manneras Example 118 from 224 mg of2-tert-butoxy-3-[4-(2-fluorobenzylthio)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.69-1.80 (2H, m), 1.99-2.08 (2H, m),2.31-2.43 (2H, m), 2.65-2.76 (1H, m), 2.91-3.00 (2H, m), 3.78 (2H, s),3.82 (2H, s), 7.03 (1H, ddd, J=9.8, 8.0, 1.2 Hz), 7.10 (1H, td, J=8.0,1.2 Hz), 7.18-7.26 (1H, m), 7.34 (1H, td, J=8.0, 2.0 Hz), 7.88 (1H, brs), 7.90 (1H, br s).

Example 412(E)-3-[4-[2-[2-(Cyclohexylmethyloxy)phenyl]vinyl]piperidino]methyl-1H-pyrazin-2-oneoxalate

The title compound (207 mg, 68% yield) was obtained in the same manneras Example 132 from 255 mg of(E)-3-[4-[2-[2-(cyclohexylmethyloxy)phenyl]vinyl]piperidino]methyl-2-methoxypyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.03-1.61 (5H, m), 1.62-2.04 (10H, m),2.34-2.46 (1H, m), 2.96-3.10 (2H, m), 3.42-3.52 (2H, m), 3.80 (2H, d,J=6.0 Hz), 4.25 (2H, br s), 6.26 (1H, dd, J=16.0, 6.8 Hz), 6.66 (1H, d,J=16.0 Hz), 6.89 (1H, t, J=7.2 Hz), 6.96 (1H, d, J=7.2 Hz), 7.19 (1H,dt, J=7.2, 1.6 Hz), 7.40 (1H, d, J=4.0 Hz), 7.44 (1H, dd, J=7.2, 1.6Hz), 7.53 (1H, d, J=4.0 Hz).

Example 4133-[4-(2-Fluorobenzylsulfonyl)piperidino]methyl-1H-pyrazin-2-one

The title compound (125 mg, 86% yield) was obtained in the same manneras Example 118 from 168 mg of2-tert-butoxy-3-[4-(2-fluorobenzylsulfonyl)piperidino]methyl-pyrazine.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.98-2.30 (6H, m), 2.79-2.88 (1H, m),3.15-3.23 (2H, m), 3.81 (2H, s), 4.30 (2H, s), 7.14 (1H, ddd, J=9.8,8.0, 1.2 Hz), 7.22 (1H, td, J=8.0, 1.2 Hz), 7.37-7.44 (1H, m), 7.53 (1H,td, J=8.0, 2.0 Hz), 7.68 (1H, br s), 7.76 (1H, br s).

Example 414trans-3-[4-[2-(2-Fluorophenyl)acetyl]-2-methylpiperidino]methyl-1H-pyrazin-2-one

The title compound (126 mg, 68% yield) was obtained in the same manneras Example 365 from 228 mg oftrans-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-2-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.15 (3H, d, J=6.8 Hz), 1.74-1.82 (1H,m), 1.87-1.98 (2H, m), 2.00-2.09 (1H, m), 2.62-2.69 (1H, m), 2.70-2.88(2H, m), 3.08-3.20 (1H, m), 3.78 (2H, s), 3.83 (1H, d, J=14.2 Hz), 4.00(1H, d, J=14.2 Hz), 7.02-7.13 (2H, m), 7.16 (1H, dt, J=7.6, 2.0 Hz),7.22-7.29 (1H, m), 7.89 (1H, d, J=2.4 Hz), 7.93 (1H, br s).

Example 415cis-3-[4-[2-(2-Fluorophenyl)acetyl]-2-methylpiperidino]methyl-1H-pyrazin-2-one

The title compound (36 mg, 95% yield) was obtained in the same manner asExample 365 from 46 mg ofcis-1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-2-methylpiperidin-4-yl]-2-(2-fluorophenyl)ethanone.

1H-NMR (400 MHz, CDCl3); δ(ppm) 1.25 (3H, d, J=6.0 Hz), 1.55-1.66 (1H,m), 1.72-1.84 (1H, m), 1.89-1.98 (2H, m), 2.31-2.40 (1H, m), 2.48-2.57(1H, m), 2.59-2.68 (1H, m), 3.03-3.10 (1H, m), 3.59 (1H, d, J=16.0 Hz),3.78 (2H, s), 4.32 (1H, d, J=16.0 Hz), 7.02-7.13 (2H, m), 7.15 (1H, dt,J=7.2, 2.0 Hz), 7.22-7.29 (1H, m), 7.85-7.95 (2H, m).

The structural formulas for the compounds obtained in the aboveProduction Examples and Examples are shown below.

TEST EXAMPLES Test Example 1

<Inhibition of Ectopic Firing>

(1) The inhibitory effect on ectopic firing was evaluated by thefollowing method, with reference to Burchiel, K J., Exp. Neurol., 102,249-253 (1988).

(2) The left saphenous nerve of rats, in which ectopic firing wasobserved, was cut near the knee joint, and approximately 3 mm was cutoff to avoid reattachment of the cut nerve. After more than a week, theleft saphenous nerve was exposed under urethane (1 g/kg body weight)anesthesia, and the proximal part up to approximately 1 cm from the cutsite was detached from the surrounding tissue. A catheter was insertedin the right cervical vein beforehand for administration of thecompound.

(3) The detached nerve was placed on a platinum hook electrode andwetted with liquid paraffin to avoid drying of the nerve. The electrodewas connected to a microelectrode amplifier, and the change in potentialwas recorded from an oscilloscope through an A/D converter onto acomputer. The recorded nerve firing was evaluated based on the number offirings in 10 seconds, using analyzing software (AcqKnowledge).

<Test Results>

Table 1 shows the inhibition of different compounds of the examplesagainst ectopic firing, for Test Example 1. An ID₅₀ of greater than 1mg/kg and up to 3 mg/kg is indicated by +, an ID₅₀ of greater than 0.5mg/kg and up to 1 mg/kg is indicated by ++, and an ID₅₀ of up to 0.5mg/kg is indicated by +++. As the results in Table 1 clearly show, thecompounds of the invention exhibited excellent inhibition of ectopicfiring.

TABLE 1 Inhibition of ectopic Example firing 122 +++ 124 +++ 127 ++ 128++ 129 ++ 132 ++ 134 ++ 135 +++ 136 ++ 137 ++ 139 ++ 140 +++ 141 +++ 142+++ 143 +++ 145 ++ 146 +++ 147 +++ 151 ++ 152 ++ 153 ++ 154 ++ 156 ++157 +++ 158 +++ 160 ++ 162 ++ 163 +++ 164 +++ 167 +++ 168 ++ 169 ++ 170+++ 171 +++ 172 ++ 174 +++ 176 ++ 177 +++ 178 +++ 179 +++ 181 +++ 183+++ 184 +++ 187 ++ 188 ++ 192 ++ 193 +++ 195 ++ 198 +++ 200 ++ 201 ++204 ++ 205 ++ 208 ++ 210 ++ 212 ++ 214 ++ 222 ++ 223 ++ 224 ++ 225 ++230 +++ 232 +++ 233 +++ 234 ++ 235 +++ 236 +++ 237 ++ 239 ++ 241 ++ 243+++ 246 ++ 251 ++ 252 ++ 253 +++ 254 ++ 256 ++ 257 +++ 258 +++ 259 +++343 +++ 344 +++ 347 +++ 350 +++ 365 +++ 373 +++ 376 +++ 394 +++ 415 +++Mexiletine +

Test Example 2

<Evaluation of Sodium Channels Using Rat Cultured Hippocampal Neurons>

(1) This experiment was conducted using rat fetal (E17-E19) culturedhippocampal neurons. The hippocampal neurons were cultured for 3-4 weeksuntil spontaneous firing occurred.

(2) The sodium-sensitive dye SBFI-AM [CAS No. 129423-53-6] (Sigma) wasadded to the hippocampal culture supernatant and incorporated thereinfor several hours at 37° C.

(3) The sodium ion concentration in the hippocampal neurons was measuredin the presence of 4-aminopyridine as an index of the SBFI fluorescentintensity. The measurement was conducted at room temperature using anFDSS2000 (Hamamatsu Photonics K.K.). In order to detect the change inintracellular sodium concentration upon addition of the test substance,the fluorescent intensity was measured immediately prior to addition ofthe test substance and 5 minutes afterwards (excitation wavelengths: 340nm and 380 nm, fluorescent wavelength: 500 nm).

(4) The sodium channel-inhibiting activity of the test substance wascalculated from the change in fluorescent intensity before and afteraddition of the test substance (fluorescent intensity at excitationwavelength of 340 nm/fluorescent intensity at excitation wavelength of380 nm). The change in fluorescent intensity using 1 μM tetrodotoxin(TTX) as a positive control was defined as 100% and the change influorescent intensity with the solution alone as a negative control wasdefined as 0%. The relative value of the change in fluorescent intensityfor the test substance was calculated as the sodium channel-inhibitingactivity (IC₅₀ (μM)).

<Test Results>

Tables 2 and 3 show the sodium channel-inhibiting activities (IC₅₀ (μM))of different compounds of the examples, for Test Example 2. As clearlyshown by the results in Tables 2 and 3, the compounds of the inventionexhibited excellent sodium channel-inhibiting activity.

TABLE 2 IC₅₀ Example (μM) 117 4.4 118 3.1 119 8.4 120 8.5 121 5.7 1247.8 125 5.0 129 2.1 132 6.2 134 3.1 135 4.0 136 4.7 140 5.6 142 4.2 1433.1 144 5.8 145 9.5 146 2.0 147 2.5 151 2.9 152 5.3 153 4.1 154 3.1 1553.5 156 4.5 168 2.1 169 3.5 170 0.4 171 0.6 172 5.0 173 4.3 174 3.6 1752.6 176 5.4 177 4.5 179 4.6 182 7.8 183 2.6 184 2.9 187 3.5 188 5.0 1897.2 190 1.2 191 7.1 192 3.8 193 2.9 194 6.6 195 2.0 196 6.2 198 1.6 2106.0 211 8.2 212 6.1 214 8.7 215 4.1 216 3.2 217 1.8 218 3.6 219 1.6 2214.9 222 2.5 223 6.0 224 1.6 225 1.6 226 4.5 235 5.0 236 7.0 238 5.6 2399.1 240 6.4 241 5.0 242 6.2 243 5.7 244 3.1 245 4.4 340 7.1 341 7.1 3423.0 343 3.5 344 4.4 345 2.1 347 3.0 348 2.6 349 8.9 350 6.0 353 1.7 3542.8 355 2.5 356 2.9 359 1.4 362 4.5 364 9.3 365 3.4 366 4.2 370 9.6 3719.0 372 3.3 373 1.6 376 1.1 388 4.7

TABLE 3 IC₅₀ Example (μM) 157 3.6 158 3.7 159 9.4 160 3.5 161 3.5 1624.6 164 3.3 165 8.4 166 8.7 167 2.3 199 6.2 200 1.6 201 6.7 202 4.9 2032.3 204 8.1 205 2.6 206 5.2 208 5.5 209 2.1 249 3.2 251 8.4 253 9.2 2548.9 255 3.1 256 5.8 258 4.2 336 4.7 337 6.5 338 9.8 394 2.8 395 6.7 3983.4 406 3.0 410 5.7 411 4.8 412 1.2 414 7.9 415 4.6

Test Example 3

<Evaluation of Cardiovascular Dynamics and Electrocardiogram inAnesthetized Dogs>

Method

Anesthetized dogs were used for the experiment. After isolating the leftand right femoral veins, a microchip pressure transducer catheter wasinserted therein, and the tip was situated near the aortic orifice andin the left ventricle, for measurement of the arterial pressure (AP) andleft ventricular pressure (LVP). The LVP was differentiated using adifferentiation unit, and the maximum value of the first derivative ofthe left ventricular pressure (LVdP/dt) (LVdP/dtmax) was used as theindex of the cariac contractility. The heart rate (HR) was measuredusing an instantaneous heart rate counter, with the LVP waveforms as thetrigger. A needle electrode was fixed to the right anterior limb andleft and right posterior limbs, and a standard II-lead electrocardiogramwas taken. The parameters were recorded on a recording sheet.

The test substance was administered through the venous catheter insertedin the femoral vein.

Administration of Test Substance and Recording

Single Administration:

The test substance was administered through the catheter for 1 minute.The electrocardiogram was recorded at 2 minutes after administration,and the change in the cardiovascular dynamic was recorded continuouslyfor 10 minutes after the administration. After 10 minutes, the dose wasincreased and the recording was repeated.

Continuous Intravenous Infusion:

The test substance was administered through the catheter for a period ofone minute, and then a sustained dose was administered by continuousintravenous infusion. The electrocardiogram was recorded at the 5 and 10minute points, and the change in cardiovascular dynamic was recordedcontinuously for 10 minutes from the start of administration. After 10minutes, the dose was increased and the recording was repeated.

Analysis

The HR, mean arterial pressure (mAP), LVdP/dtmax and electrocardiogramparameters (RR interval, PQ interval, QRS interval, QT interval) wereread from the recording sheet. The QT interval was heart rate-correctedand represented as the QTc interval.

<Test Results>

Tables 4 to 8 show the changes in the electrocardiogram parameters uponsingle administration of known sodium channel inhibitors for TestExample 3. The numbers in the tables indicate the percent changes withrespect to the measured values prior to administration of each sodiumchannel inhibitor. As clearly shown by the results in Tables 4 to 8, theknown sodium channel-inhibiting compounds such as Mexiletine,Pilsicamide, Flecamide, Aprindine and Amitriptyline exhibited effects onthe cardiovascular system.

TABLE 4 Mexiletine Dose PQ QRS QTc (mg/kg weight) HR mAP LVdP/dtinterval interval interval 2.2 −2.8 −6.2 −20.8 0.7 1.8 −3.0 6.6 −10.6−44.2 −47.8 3.4 6.3 −4.6

TABLE 5 Pilsicainide Dose PQ QRS QTc (mg/kg weight) HR mAP LVdP/dtinterval interval interval 1 −1.0 −3.2 −20.6 17.4 4.6 3 −5.0 −8.2 −31.755.1 5.3

TABLE 6 Flecainide Dose PQ QRS QTc (mg/kg weight) HR mAP LVdP/dtinterval interval interval 1 −8.6 −14.2 −18.2 8.8 6.4 2.3 3 −24.8 −42.9−56.9 36.1 37.1 9.3

TABLE 7 Aprindine Dose PQ QRS QTc (mg/kg weight) HR mAP LVdP/dt intervalinterval interval 2 −12.8 −34.7 −29 14.2 4.5 4 −19.2 −47.7 −47.5 36.8−0.4

TABLE 8 Amitriptyline Dose PQ QRS QTc (mg/kg weight) HR  mAP LVdP/dtinterval interval interval 0.3 −2.9 −0.9 −5.9 −1.5 0.4 1.9 1 −4.0 −25.4−21.7 8.7 15.4 13.1

In Test Example 3, the effects of the representative compounds of theinvention on the cardiovascular system were also evaluated, and it wasconfirmed that single administration at 1 mg/kg body weight and greaterproduced virtually no effect on the HR, mean arterial pressure (mAP),LVdP/dtmax and electrocardiogram parameters (RR interval, PQ interval,QRS interval, QT interval).

Test Example 4

<Evaluation of Drug Metabolizing Enzyme (Cytochrome P450)>

This experiment was conducted using an activity measuring kit (GENTES)employing a P450 recombinant expression system and a fluorescentsubstrate, following the included instruction manual, and the inhibitingactivity IC₅₀ was calculated. The evaluated P450 molecular species werethe following five: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and thelike. The experiment conditions were as shown below. A plate reader(CYTO FLUOR Multi-Well Plate Reader Series 4000, by PerSeptiveBiosystems) was used for measurement of the fluorescent intensity. Theinhibition strength was measured 9 times each second and the averagevalue was calculated, based on the intensity of fluorescence emitted bythe fluorescent substrate metabolite.

The substrates, metabolites, inhibitors, excitation wavelengths andfluorescent wavelengths used for the measurement are shown in Table 9.

TABLE 9 excitation emission wave- wave- P450 sub- meta- length lengthspeices strate bolite inhibitor (nm) (nm) CYP1A2 CEC CHC Furafyline 409460 CYP2C9 MFC HFC Sulfaphenazole 409 530 CYP2C19 CEC CHCTranylcypromine 409 460 CYP2D6 AMMC AHMC Quinidine 390 460 CYP3A4 BFCHFC Ketoconazole 409 530

The abbreviations used to represent the substrates and metabolites areshown below in Table 10.

TABLE 10 CEC 3-Cyano-7-ethoxycoumarin CHC 3-Cyano-7-hydroxycoumarin MFC7-Methoxy-4-trifluoromethylcoumarin HFC7-Hydroxy-4-trifluoromethylcoumarin CEC 7-Ethoxy-3-cyanocoumarin CHC7-Hydroxy-3-cyanocoumarin AMMC3-[2-(N,N-diethyl-N-methylamino)ethyl]-7-methoxy-4- methylcoumarin AHMC3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4-methylcoumarin BFC7-Benzyloxy-4-(trifluoromethyl)-coumarin HFC7-hydroxy-4-(trifluoromethyl)-coumarin<Test Results>

As a result of evaluating the metabolic inhibition of the compounds ofthe invention against P450 for Test Example 4, it was confirmed that therepresentative compounds of the invention exhibit an IC₅₀ of 10 μM orgreater for the following five P450 molecular species: CYP1A2, CYP2C9,CYP2C19, CYP2D6, CYP3A4.

Test Example 5

<Inhibition of hERG Channel Current>

(1) The inhibiting effect on hERG channel current was evaluated withreference to Zhou, Z. et al., Biophysical Journal, 74, 230-241 (1998).

(2) The experiment was conducted using HEK-293 cells introduced the hERGchannel gene (subtype 1) (cell line established by this company).

(3) From one to several days prior to the experiment, the cells wereseeded onto a polylysine-coated glass plate and cultured up to the dayof the experiment. At the start of the experiment, the cell-seeded glassplate was transferred to a current measuring bath. The hERG channelcurrent was observed by the voltage-clamp method using a patch clamp.The measurement was conducted using a current amplifier (AxonInstruments), and the current was recorded and analyzed using pCLAMPsoftware (Axon Instruments).

(4) The hERG channel current was induced by applying to the cells adepolarizing pulse from a holding potential of −80 mV to +20 mV for 5seconds and to −50 mV for 4 seconds, at 20 second intervals. Uponstabilization of the current in normal solution, perfusion was carriedout with solutions containing the test compound at differentconcentrations.

(5) The amplitude of the hERG channel current was defined as the peakvalue of the tail current observed upon restoring the potential to −50mV. The inhibiting effect (IC₅₀) of the test compound on the hERGchannel current was calculated based on the change in the peak value ofthe tail current recorded with addition of the test compound at eachconcentration, with respect to the peak value of the tail currentrecorded in normal solution as 100%.

<Test Results>

As a result of evaluating the inhibiting effects of the representativecompounds of the invention against hERG channel current for Test Example˜5, they were found to exhibit IC₅₀ values of 10 μM or greater.

INDUSTRIAL APPLICABILITY

As explained above, the present invention provides novel nitrogencontaining heterocyclic compounds which have excellent sodiumchannel-inhibiting activity and are highly useful as medicines ingeneral consideration of their pharmacological activity and safety (interms of effects on the cardiovascular system, inhibiting action on drugmetabolizing enzymes, enzyme induction, etc.), as well as salts thereofand novel pharmaceutical compositions comprising them. The compounds ofthe invention and pharmaceutical compositions comprising them exhibitexcellent therapeutic or prophylactic effects against diseases whereinsodium channel inhibition is effective as treatment and prevention, suchas various types of neuralgia (for example, diabetic neuralgia, HIVneuralgia, postherpetic neuralgia, trigeminal neuralgia, stump pain,post spinal injury pain, thalamic pain, post-stroke pain, etc.),neuropathy, epilepsy, insomnia, premature ejaculation, and the like, andare therefore useful as therapeutic or prophylactic agents andanalgesics.

1. A compound represented by the following formula:

or a salt thereof, wherein: X¹ represents single bond; X² representsmethylene, 1,2-ethylene or 1,1-ethylene; —X³—X⁴- is methylene, oxygen, asingle bond or a group represented by the formula:

wherein X⁴⁰ represents (1) methylene optionally having 1 or 2 groupsselected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy and cyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)—or (6)—S(O)₂—; X⁴¹ represents methylene optionally having 1 or 2 groupsselected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy and cyano; R³⁴ represents C₁₋₆ alkyl; R⁴¹ represents (1)phenyl optionally having 1 to 3 groups selected from the groupconsisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy and cyano, (2)phenyl-C₁₋₆ alkyl optionally having 1 to 3 groups selected from thegroup consisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy and cyanoor (3) C₁₋₆ alkyl optionally having 1 to 3 groups selected from thegroup consisting of halogen, hydroxyl, C₁₋₆ alkoxy and cyano; and R⁴²represents (1) C₁₋₆ alkyl optionally having 1 to 3 groups selected fromthe group consisting of halogen, hydroxyl, C₁₋₆ alkoxy and cyano or (2)hydrogen; Z¹ represents a group represented by the formula:

wherein R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ each independently represent (1)hydrogen, (2) halogen, (3) cyano, (4) hydroxyl, (5) C₂₋₇ alkoxycarbonyl,(6) C₁₋₆ alkyl optionally substituted with 1 to 4 groups selected fromthe group consisting of hydroxyl, C₁₋₆ alkoxy and halogen, (7) C₁₋₆alkoxy optionally substituted with 1 to 4 groups selected from the groupconsisting of hydroxyl, C₁₋₆ alkoxy and halogen, (8)2-methylphenyloxymethyl or (9) 2-fluorophenyloxymethyl, and at least oneof R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ is not hydrogen; A² represents optionallysubstituted phenyl, optionally substituted 1-naphthyl, optionallysubstituted 2-naphthyl, an optionally substituted 5- to 10-memberedaromatic heterocyclic group, an optionally substituted 9- to 11-memberedbenzene fused ring group or an optionally substituted 9- to 11-memberedaromatic heterocycle fused ring group; wherein an optional substituenton A² is selected from Substituent Group A below; Substituent Group Aconsists of C₁₋₆ alkyl optionally having 1 to 3 substituents selectedfrom Substituent Group B below, C₁₋₆ alkoxy optionally having 1 to 3substituents selected from Substituent Group B below, halogen, C₃₋₈cycloalkyl, C₂₋₇ alkoxycarbonyl, C₂₋₇ acyl, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, cyano, nitro, phenyl, pyridyl,ethylenedioxy, methylenedioxy, a group represented by the formula:

wherein t1 and t2 each independently represent an integer of 0 to 3, andR⁸⁰ represents hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl, and a grouprepresented by the formula:

wherein R⁷³ and R⁷⁴ each independently represent hydrogen, C₁₋₆ alkyl,C₂₋₇ acyl, C₁₋₆ alkylsulfonyl, —CO—NR⁷⁵R⁷⁶ or —CS—NR⁷⁵R⁷⁶, and R⁷⁵ andR⁷⁶ each independently represent hydrogen or C₁₋₆ alkyl; and SubstituentGroup B consists of halogen, C₁₋₆ alkoxy, cyano, hydroxyl and C₃₋₈cycloalkyl; and A^(l) represents a group represented by the formula:

wherein R²¹ represents hydrogen or C₁₋₆ alkyl, and R^(61a), R^(62a)andR^(63a) each independently represent hydrogen, halogen, C₁₋₆ alkoxy,C₁₋₆ alkyl or cyano.
 2. The compound according to claim 1, wherein R⁵¹,R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ each independently represent (1) hydrogen, (2)hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, (5) cyano or (6) hydroxymethyl,and at least one of R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ is not hydrogen.
 3. Thecompound according to claim 1, wherein one of R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷is not hydrogen and four of R⁵¹, R⁵³, R⁵⁴, R⁵⁵ and R⁵⁷ are hydrogen. 4.The compound according to claim 1, wherein —X³—X⁴—is a group representedby the formula:

wherein X⁴ is (1) methylene optionally having one group selected fromthe group consisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy andcyano, (2) oxygen, (3) —CO—, (4) —S—, (5) —S(O)—, or (6) —S(O)₂—, andX⁴¹ is either methylene optionally having one group selected from thegroup consisting of halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy andcyano.
 5. The compound according to claim 1, wherein —X³—X⁴—is a grouprepresented by the formula:


6. The compound according to claim 1, wherein A² is phenyl optionallyhaving 1 to 3 substituents selected from Substituent Group A, 1-naphthyloptionally having 1 to 3 substituents selected from Substituent Group A,2-naphthyl optionally having 1 to 3 substituents selected fromSubstituent Group A, a 5- to 10-membered aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from Substituent Group A,a 9- to 11-membered benzene fused ring group optionally having 1 to 3substituents selected from Substituent Group A-or a 9- to 11-memberedaromatic heterocycle fused ring group optionally having 1 to 3substituents selected from Substituent Group A.
 7. The compoundaccording to claim 1, wherein A² is a monovalent group derived byremoving a hydrogen atom from a compound represented by the formula:

and A² optionally has 1 to 3 substituents selected from SubstituentGroup A.
 8. The compound according to claim 1, wherein A² is amonovalent group derived by removing a hydrogen atom from a compoundrepresented by the formula:

and A² optionally has 1 to 3 substituents selected from SubstituentGroup A.
 9. The compound according to claim 6, wherein Substituent GroupA is the group consisting of halogen, C₁₋₆ alkyl optionally having 1 to3 substituents selected from Substituent Group B, C₁₋₆ alkoxy optionallyhaving 1 to 3 substituents selected from Substituent Group B, C₃₋₈cycloalkyl, C₁₋₆ alkylthio and a group represented by the formula:

wherein t1 and t2 each independently represent an integer of 0 to 3, andR⁸⁰ represents hydrogen, C₁₋₆ alkyl or C₃₋₈ cycloalkyl.
 10. The compoundaccording to claim 1, wherein A² is a group represented by the formula:

wherein R⁸⁰ represents (1) C₁₋₆ alkyl optionally having 1 to 3substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl and C₁₋₆ alkoxy, (2) C₁₋₆ alkoxy optionally having 1 to 3substituents selected from the group consisting of halogen, C₃₋₈cycloalkyl and C₁₋₆ alkoxy, (3) hydrogen, (4) C₁₋₆ alkylthio optionallyhaving 1 to 3 substituents selected from the group consisting ofhalogen, C₃₋₈ cycloalkyl and C₁₋₆ alkoxy or (5) halogen.
 11. Thecompound according to claim 1, wherein A² is a group represented by theformula:


12. The compound according to claim 1, wherein R²¹ is hydrogen.
 13. Thecompound according claim 1, wherein R ^(61a) and R^(62a) are hydrogen.14. A pharmaceutical composition, comprising a compound of claim 1, anda pharmaceutically acceptable carrier.
 15. The compound according toclaim 1, wherein R⁵¹, R⁵³, R⁵⁵ and R⁵⁷ each independently represent (1)hydrogen, (2) halogen, (3) cyano, (4) hydroxyl, (5) C₂₋₇ alkoxycarbonyl,(6) C₁₋₆ alkyl optionally substituted with 1 to 4 groups selected fromthe group consisting of hydroxyl, C₁₋₆ alkoxy and halogen, (7) C₁₋₆alkoxy optionally substituted with 1 to 4 groups selected from the groupconsisting of hydroxyl, C₁₋₆ alkoxy and halogen, (8)2-methylphenyloxymethyl or (9) 2-fluorophenyloxymethyl, and R⁵⁴represents (1) halogen, (2) cyano, (3) hydroxyl, (4) C₂₋₇alkoxycarbonyl, (5) C₁₋₆ alkyl optionally substituted with 1 to 4 groupsselected from the group consisting of hydroxyl, C₁₋₆ alkoxy and halogen,(6) C₁₋₆ alkoxy optionally substituted with 1 to 4 groups selected fromthe group consisting of hydroxyl, C₁₋₆ alkoxy and halogen, (7)2-methylphenyloxymethyl or (8) 2-fluorophenyloxymethyl.
 16. The compoundaccording to claim 15, wherein R⁵¹, R⁵³, R⁵⁵, and R⁵⁷ representhydrogen.